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1.  Synergistic activity and mechanism of action of Stephania suberosa Forman extract and ampicillin combination against ampicillin-resistant Staphylococcus aureus 
Background
Ampicillin-resistant S. aureus (ARSA) now poses a serious problem for hospitalized patients, and their care providers. Plant-derived antibacterial that can reverse the resistance to well-tried agents which have lost their original effectiveness are the research objectives of far reaching importance. To this aim, the present study investigated antibacterial and synergistic activities of Stephania suberosa extracts (SSE) against ARSA when used singly and in combination with ampicillin.
Results
The majority chemical compounds of SSE were alkaloid (526.27 ± 47.27 mg/1 g of dried extract). The Minimum inhibitory concentration (MICs) for ampicillin and SSE against all ARSA strains were >512 μg/ml and 4 mg/ml, respectively. Checkerboard assay revealed synergistic activity in the combination of ampicillin (0.15 μg/ml) and SSE (2 mg/ml) at fractional inhibitory concentration index (FICI) <0.5. The killing curve assay had confirmed that the viability of ARSA was dramatically reduced from 5x105 cfu/ml to 103 cfu/ml within 6 h after exposure to SSE (2 mg/ml) plus ampicillin (0.15 μg/ml) combination. Electron microscopic study clearly revealed that these ARSA cells treated with this combination caused marked morphological damage, peptidoglycan and cytoplasmic membrane damage, and average cell areas significant smaller than control. Obviously, Immunofluorescence staining and confocal microscopic images confirmed that the peptidoglycan of these cells were undoubtedly disrupted by this combination. Furthermore, the CM permeability of ARSA was also increased by this combination. Enzyme assay demonstrated that SSE had an inhibitory activity against β-lactamase in concentrations manner.
Conclusions
So, these findings provide evidence that SSE has the high potential to reverse bacterial resistance to originate traditional drug susceptibility of it and may relate to three modes of actions of SSE: (1) inhibits peptidoglycan synthesis, resulting in morphological damage, (2) inhibits β-lactamases activity, and (3) increases CM permeability. It is widely recognized that many types of drugs are derived from alkaloids. So, this SSE offers the prominent potential to develop a novel adjunct phytopharmaceutical to ampicillin for the treatment of ARSA. Further active ingredients study, toxicity of it, and the synergistic effect on blood and tissue should be performed and confirmed in an animal test or in humans.
doi:10.1186/s12929-014-0090-2
PMCID: PMC4428530  PMID: 25208614
β-lactam antibiotics; Ampicillin-resistant S. aureus (ARSA) Stephania suberosa Forman; Synergistic activity; Ampicillin
2.  The joint in vitro action of polymyxin B and miconazole against pathogens associated with canine otitis externa from three European countries 
Veterinary Dermatology  2013;24(4):439-e97.
Background
Canine otitis externa, an inflammation of the external ear canal, can be maintained and worsened by bacterial or fungal infections. For topical treatment, combinations of anti-inflammatory and antimicrobial ingredients are mainly used.
Hypothesis/Objectives
This study was conducted to elucidate the in vitro activity of polymyxin B and miconazole against clinical bacterial isolates from three European countries, to investigate possible differences in sensitivity and to assess drug interactions.
Animals
Seventeen strains of Escherichia coli, 24 strains of Pseudomonas aeruginosa, 24 strains of Proteus mirabilis and 25 strains of Staphylococcus pseudintermedius from dogs with diagnosed otitis externa had been isolated in Germany, France and Italy.
Methods
Drug activities were evaluated by minimal inhibitory concentration (MIC) and minimal bactericidal concentration. The potentiation of polymyxin B plus miconazole was calculated using the fractional inhibitory concentration index (FICI). An FICI ≤0.5 defined synergy. Furthermore, geographical variations in the FICI and MIC were assessed by statistical analysis.
Results
Bacterial susceptibilities were comparable in different European countries, because there were no significant MIC and FICI variations (P > 0.05). As a single agent, polymyxin B had bactericidal activity against most E. coli and P. aeruginosa strains and, in higher concentrations, against S. pseudintermedius strains. Miconazole was bactericidal against all Staphylococcus strains. Synergy was demonstrated against strains of E. coli and P. aeruginosa (FICI = 0.25 and 0.50, respectively), whereas overall there was no interaction against S. pseudintermedius strains (FICI = 1.25). Proteus mirabilis strains were not inhibited by each of the drugs individually or by their combination.
Conclusions and clinical importance
In vitro synergy of polymyxin B and miconazole against E. coli and P. aeruginosa isolates indicates a rationale for applying both agents in combination to treat otitis externa when infected with these types of bacteria.
Résumé
Contexte
L'otite externe canine, une inflammation du conduit auriculaire externe, peut être entretenue et aggravée par les infections bactériennes ou fongiques. Pour le traitement topique, les associations d'anti-inflammatoires et d'antimicrobiens sont principalement utilisées.
Hypothèses/Objectifs
Cette étude a été menée pour déterminer l'activité in vitro de la polymyxine B et du miconazole contre les souches bactériennes cliniques isolées dans trois pays européens, d'étudier les différences possibles de sensibilité et de déterminer les interactions médicamenteuses.
Sujets
Dix-sept souches d'Escherichia coli, 24 souches de Pseudomonas aeruginosa, 24 souches de Proteus mirabilis et 25 souches de Staphylococcus pseudintermedius ont été isolées de chiens atteints d'otite externe en Allemagne, France et Italie.
Résultats
L'activité des molécules a été évaluée par la concentration minimale inhibitrice (CMI) et la concentration minimale bactéricide. La potentialisation de la polymyxine B et du miconazole a été calculée par l'indice de concentration inhibitrice fractionnaire (FICI). Un FICI ≤ 0.5 définissait la synergie. En outre, les variations géographiques dans le FICI et la CMI étaient évaluées par analyses statistiques.
Résultats
Les sensibilités bactériennes étaient comparables dans les différents pays européens parce qu'aucune différence significative n'a été mise en évidence entre les variations de CMI et de FICI (P > 0.05). La polymyxine B en tant que seul agent avait une activité bactéricide contre la plupart des souches de E. coli et P. aeruginosa, et, à plus forte concentration, contre les souches de S. pseudintermedius. Le miconazole était bactéricide contre toutes les souches de S. pseudintermedius. Une synergie a été mise en évidence contre les souches de E. coli et P. aeruginosa (FICI = 0.25 et 0.50, respectivement), alors qu'aucune interaction n'a été mise en évidence contre les souches de S. pseudintermedius (FICI = 1.25). Les souches de Proteus mirabilis n'ont été inhibées par aucune des molécules, individuellement ou en association.
Conclusions et importance clinique
La synergie in vitro de la polymyxine B et du miconazole contre les souches d'E. coli et de P. aeruginosa justifie l'application de la combinaison des deux agents dans le traitement de l'otite externe lors d'infection par ces bactéries.
Resumen
Introducción
la otitis externa canina, inflamación del canal auditivo externo, puede perpetuarse y empeorar debido a la presencia de infecciones bacterianas o fúngicas. Para el tratamiento tópico se utilizan fundamentalmente combinaciones de ingredientes antiinflamatorios y antimicrobianos.
Hipótesis/objetivos
este estudio se condujo para elucidar la actividad in vitro de polimixina B y miconazol frente a aislados clínicos bacterianos de tres países europeos, investigar posibles diferencias en sensibilidad y analizar interacciones de fármacos.
Animales
diecisiete cepas de Escherichia coli, 24 cepas de Pseudomonas aeruginosa, 24 cepas de Proteus mirabilis y 25 cepas de Staphylococcus pseudintermedius de perros diagnosticados con otitis externa asilados de Alemania, Francia e Italia.
Métodos
se evaluó la actividad de los fármacos mediante la concentración inhibitoria minima (MIC) y la concentración bactericida minima. La potenciación de polimixina B y miconazol se calculó usando el índice de concentración fraccional inhibitoria (FICI). Un FICI≤ 0,5 definía sinergismo. Además se analizaron estadísticamente las variaciones en la FICI y MIC dependiendo de la región de origen.
Resultados
la susceptibilidad bacteriana fue comparable en los diferentes países europeos ya que no hubo diferencias significativas en MIC y FICI (P > 0,05). Como agente único la polimixina B tuvo actividad antimicrobiana frente a la mayoría de cepas de E. coli y P. aeruginosa, y a mayores concentraciones frente a cepas de S. pseudintermedius. El miconazol fue bactericida frente a todas las cepas de Staphylococcus. Se observó sinergismo frente a cepas de E. coli y P. aeruginosa (FICI = 0.25 y 0,50, respectivamente), mientras en general no hubo sinergismo frente a las cepas de S. pseudintermedius (FICI = 1.25). Cepas de Proteus mirabilis no fueron inhibidas por los fármacos individualmente ni en combinación.
Conclusiones e importancia clínica
el sinergismo in vitro de la polimixina B y el miconazol frente a aislados de E. coli y P. aeruginosa indica un motivo para utilizar ambos agentes en combinación para tratar casos de otitis externa producidos por infecciones con estas bacterias.
Zusammenfassung
Hintergrund
Die canine Otitis externa, eine Entzündung des äußeren Ohrkanals, kann durch eine bakterielle Infektion oder durch eine Infektion mit Hefepilzen aufrechterhalten bzw. verschlimmert werden. Zur topischen Behandlung werden hauptsächlich Kombinationen aus entzündungshemmenden und antimikrobiellen Wirkstoffen verwendet.
Hypothese/Ziele
Diese Studie wurde durchgeführt, um die in vitro Aktivität von Polymyxin B und Mikonazol gegenüber klinischen Bakterienisolaten aus drei europäischen Ländern zu beleuchten und um mögliche Unterschiede in der Sensibilität zu untersuchen und um Interaktionen von Medikamenten zu beurteilen.
Tiere
Siebzehn Stämme von Escherichia coli, 24 Stämme von Pseudomonas aeruginosa, 24 Stämme von Proteus mirabilis und 25 Stämme von Staphylokokkus pseudintermedius von Hunden mit einer diagnostizierten Otitis externa waren in Deutschland, Frankreich und Italien isoliert worden.
Methoden
Die Wirkstoffaktivitäten wurden mittels minimaler inhibitorischer Konzentration (MIC) und minimaler bakterizider Konzentration evaluiert. Die Potenzierung von Polymyxin B plus Mikonazol wurde mittels „Fractional Inhibitory Concentration Index” (FICI) kalkuliert. Ein FICI ≤ 0,5 definierte eine Synergie. Weiters wurden geographische Variationen des FICI und der MIC mittels statistischer Analyse beurteilt.
Ergebnisse
Die bakteriellen Empfindlichkeiten waren in den verschiedenen europäischen Ländern vergleichbar, da keine signifikanten Unterschiede bei MIC und FICI bestanden (P > 0,05). Als alleiniger Wirkstoff zeigte Polymyxin B eine bakterizide Wirkung gegenüber den meisten E. coli und P. aeruginosa Stämmen und, in höheren Konzentrationen, gegenüber S. pseudintermedius Stämmen. Eine Synergie wurde gegen E. coli und P. aeruginosa Stämme (FICI = 0.25 bzw. 0,50) demonstriert, während insgesamt keine Interaktion gegen S. pseudintermedius Stämme (FICI = 1.25) bestand. Proteus mirabilis Stämme wurden von keinem dieser Wirkstoffe, weder individuell noch in Kombination, inhibiert.
Schlussfolgerungen und klinische Bedeutung
Eine in vitro Synergie von Polymyxin B und Mikonazol gegenüber E. coli und P. aeruginosa Isolaten bekräftigt die Argumentation dafür, beide Wirkstoffe in Kombination zu verwenden, um eine Otitis externa, bei der diese Bakterien vorkommen, zu behandeln.
doi:10.1111/vde.12037
PMCID: PMC4240513  PMID: 23721182
3.  Anti-nociceptive properties in rodents and the possibility of using polyphenol-rich fractions from sida urens L. (Malvaceae) against of dental caries bacteria 
Background
Sida urens L. (Malvaceae) is in flora of Asian medicinal herbs and used traditionally in West of Burkina Faso for the treatment of infectious diseases and particularly used against, dental caries bacteria, fever, pain and possesses analgesic properties. This study was conducted to reveal the antibacterial effect against dental caries bacteria on the one hand, and evaluate their analgesic capacity in experimental model with Swiss mice and on the other hand, with an aim to provide a scientific basis for the traditional use of this plant for the management of dental caries bacteria.
Method
The antibacterial assays in this study were performed by using inhibition zone diameters, MIC (Minimum inhibitory concentration) and MBC (Minimal bactericidal concentration) methods. On the whole the dental caries bacteria (Gram-positive and Gram-negative bacterial strains) were used. Negative control was prepared using discs impregnated with 10% DMSO in water and commercially available Gentamicin from Alkom Laboratories LTD was used as positive reference standards for all bacterial strains. In acute toxicity test, mice received doses of extract (acetone/water extract) from Sida urens L. by intraperitoneal route and LD50 was determined in Swiss mice. As for analgesic effects, acetic acid writhing method was used in mice. The acetic acid-induced writhing method was used in mice with aim to study analgesic effects.
Results
The results showed that the highest antibacterial activities were founded with the polyphenol-rich fractions against all bacterial strains compared to the standard antibiotic. About preliminary study in acute toxicity test, LD50 value obtained was more than 5000 mg/kg b.w. Polyphenol-rich fractions produced significant analgesic effects in acetic acid-induced writhing method and in a dose-dependent inhibition was observed.
Conclusion
These results validate the ethno-botanical use of Sida urens L. (Malvaceae) and demonstrate the potential of this herbaceous as a potential antibacterial agent of dental caries that could be effectively used for future health care purposes.
doi:10.1186/1476-0711-12-14
PMCID: PMC3699430  PMID: 23787152
4.  Isojacareubin from the Chinese Herb Hypericum japonicum: Potent Antibacterial and Synergistic Effects on Clinical Methicillin-Resistant Staphylococcus aureus (MRSA) 
Through bioassay-guided fractionation of the extracts from the aerial parts of the Chinese herb Hypericum japonicum Thunb. Murray, Isojacareubin (ISJ) was characterized as a potent antibacterial compound against the clinical methicillin-resistant Staphylococcus aureus (MRSA). The broth microdilution assay was used to determine the minimal inhibitory concentrations (MICs) and minimal bactericidal concentrations (MBCs) of ISJ alone. The results showed that its MICs/MBCs ranged from 4/16 to 16/64 μg/mL, with the concentrations required to inhibit or kill 50% of the strains (MIC50/MBC50) at 8/16 μg/mL. Synergistic evaluations of this compound with four conventional antibacterial agents representing different types were performed by the chequerboard and time-kill tests. The chequerboard method showed significant synergy effects when ISJ was combined with Ceftazidime (CAZ), Levofloxacin (LEV) and Ampicillin (AMP), with the values of 50% of the fractional inhibitory concentration indices (FICI50) at 0.25, 0.37 and 0.37, respectively. Combined bactericidal activities were also observed in the time-kill dynamic assay. The results showed the ability of ISJ to reduce MRSA viable counts by log10CFU/mL at 24 h of incubation at a concentration of 1 × MIC were 1.5 (LEV, additivity), 0.92 (CAZ, indifference) and 0.82 (AMP, indifference), respectively. These in vitro anti-MRSA activities of ISJ alone and its synergy with conventional antibacterial agents demonstrated that ISJ enhanced their efficacy, which is of potential use for single and combinatory therapy of patients infected with MRSA.
doi:10.3390/ijms13078210
PMCID: PMC3430230  PMID: 22942699
anti-MRSA activity; Hypericum japonicum; Isojacareubin; MIC; synergy
5.  Antibiotic additive and synergistic action of rutin, morin and quercetin against methicillin resistant Staphylococcus aureus 
Background
To determine the effect of flavonoids in conjunction with antibiotics in methicillin resistant Staphylococcus aureus (MRSA) a study was designed. The flavonoids included Rutin, Morin, Qurecetin while antibiotics included ampicillin, amoxicillin, cefixime, ceftriaxone, vancomycin, methicillin, cephradine, erythromycin, imipenem, sulphamethoxazole/trimethoprim, ciprofloxacin and levolfloxacin. Test antibiotics were mostly found resistant with only Imipenem and Erythromycin found to be sensitive against 100 MRSA clinical isolates and S. aureus (ATCC 43300). The flavonoids were tested alone and also in different combinations with selected antibiotics.
Methods
Antibiotics and flavonoids sensitivity assays were carried using disk diffusion method. The combinations found to be effective were sifted through MIC assays by broth macro dilution method. Exact MICs were determined using an incremental increase approach. Fractional inhibitory concentration indices (FICI) were determined to evaluate relationship between antibiotics and flavonoids is synergistic or additive. Potassium release was measured to determine the effect of antibiotic-flavonoids combinations on the cytoplasmic membrane of test bacteria.
Results
Antibiotic and flavonoids screening assays indicated activity of flavanoids against test bacteria. The inhibitory zones increased when test flavonoids were combined with antibiotics facing resistance. MICs of test antibiotics and flavonoids reduced when they were combined. Quercetin was the most effective flavonoid (MIC 260 μg/ml) while morin + rutin + quercetin combination proved most efficient with MIC of 280 + 280 + 140 μg/ml. Quercetin + morin + rutin with amoxicillin, ampicillin, cephradine, ceftriaxone, imipenem, and methicillin showed synergism, while additive relationship was indicated between morin + rutin and amoxicillin, cephradine, ceftriaxone, imipenem, and methicillin. Quercetin alone had an additive effect with ampicillin, cephradine, ceftriaxone, imipenem, and methicillin. Potassium leakage was highest for morin + rutin + quercetin that improved further in combination with imipenem. Morin and rutin alone had no activity but in combination showed activity against test bacteria.
Conclusions
The flavonoids when used in combination with antibiotics were found to increase each other activity against test bacteria. The relationship between the flavonoids and antibiotics in most of the cases was additive. However in a few cases synergism was also observed. Flavonoids alone or in combinations also damaged bacterial cell membrane.
doi:10.1186/s12906-015-0580-0
PMCID: PMC4364681  PMID: 25879586
Morin; Rutin; Quercetin; MRSA
6.  In Vitro Synergistic Effect of Psidium guineense (Swartz) in Combination with Antimicrobial Agents against Methicillin-Resistant Staphylococcus aureus Strains 
The Scientific World Journal  2012;2012:158237.
The aim of this study was to evaluate the antimicrobial activity of aqueous extract of Psidium guineense Swartz (Araçá-do-campo) and five antimicrobials (ampicillin, amoxicillin/clavulanic acid, cefoxitin, ciprofloxacin, and meropenem) against twelve strains of Staphylococcus aureus with a resistant phenotype previously determined by the disk diffusion method. Four S. aureus strains showed resistance to all antimicrobial agents tested and were selected for the study of the interaction between aqueous extract of P. guineense and antimicrobial agents, by the checkerboard method. The criteria used to evaluate the synergistic activity were defined by the fractional inhibitory concentration index (FICI). All S. aureus strains were susceptible to P. guineense as determined by the microdilution method. The combination of the P. guineense extract with the antimicrobial agents resulted in an eight-fold reduction in the MIC of these agents, which showed a FICI ranging from 0.125 to 0.5, suggesting a synergistic interaction against methicillin-resistant Staphylococcus aureus (MRSA) strains. The combination of the aqueous extract of P. guineense with cefoxitin showed the lowest FICI values. This study demonstrated that the aqueous extract of P. guineense combined with beta lactamics antimicrobials, fluoroquinolones, and carbapenems, acts synergistically by inhibiting MRSA strains.
doi:10.1100/2012/158237
PMCID: PMC3349319  PMID: 22619603
7.  Free radical scavenging capacity, anticandicidal effect of bioactive compounds from Sida Cordifolia L., in combination with nystatin and clotrimazole and their effect on specific immune response in rats 
Background
Infectious diseases caused by fungi are still a major threat to public health, despite numerous efforts by researchers. Use of ethnopharmacological knowledge is one attractive way to reduce empiricism and enhance the probability of success in new drug-finding efforts. In this work, the total alkaloid compounds (AC) from Sida cordifolia L. (Malvaceae) have been investigated for their free radical scavenging capacity, antifungal and immunostimulatory properties.
Method
The antifungal activity was investigated against five candida strains using the microplate dilution method and the Fractional Inhibitory Concentration Index (FICI) of compounds was evaluated. The antioxidant activity of the samples was evaluate using three separate methods, at last, the immunostimulatory effect on immunosuppressed wistar rats was performed.
Results
As for the antifungal activity, result varied according to microorganism. The results obtained in this antifungal activity were interesting and indicated a synergistic effect between alkaloid compounds and the antifungal references such as Nystatin and Clotrimazole. Antioxidant capacity noticed that the reduction capacity of DPPH radicals obtained the best result comparatively to the others methods of free radical scavenging. Our results showed a low immunostimulatory effect and this result could be explained by the lack of biologically active antioxidants such as polyphenol compounds lowly contained in the alkaloid compounds.
Conclusion
The results of this study showed that alkaloid compounds in combination with antifungal references (Nystatin and Clotrimazole) exhibited antimicrobial effects against candida strains tested. The results supported the utilization of these plants in infectious diseases particularly in treatment of candida infections.
doi:10.1186/1476-0711-11-33
PMCID: PMC3576270  PMID: 23268761
8.  Synergistic antimicrobial activity between pentacyclic triterpenoids and antibiotics against Staphylococcus aureus strains 
Background
There has been considerable effort to discover plant-derived antibacterials against methicillin-resistant strains of Staphylococcus aureus (MRSA) which have developed resistance to most existing antibiotics, including the last line of defence, vancomycin. Pentacyclic triterpenoid, a biologically diverse plant-derived natural product, has been reported to show anti-staphylococcal activities. The objective of this study is to evaluate the interaction between three pentacyclic triterpenoid and standard antibiotics (methicillin and vancomycin) against reference strains of Staphylococcus aureus.
Methods and Results
The activity of the standard antibiotics and compounds on reference methicillin-sensitive and resistant strains of S. aureus were determined using the macrodilution broth method. The minimum inhibitory concentration (MIC) of the compounds was compared with that of the standard antibiotics. The interaction between any two antimicrobial agents was estimated by calculating the fractional inhibitory concentration (FIC index) of the combination. The various combinations of antibiotics and compounds reduced the MIC to a range of 0.05 to 50%.
Conclusion
Pentacyclic triterpenoids have shown anti-staphylococcal activities and although individually weaker than common antibiotics produced from bacteria and fungi, synergistically these compounds may use different mechanism of action or pathways to exert their antimicrobial effects, as implicated in the lowered MICs. Therefore, the use of current antibiotics could be maintained in their combination with plant-derived antibacterial agents as a therapeutic option in the treatment of S. aureus infections.
doi:10.1186/1476-0711-10-25
PMCID: PMC3127748  PMID: 21658242
9.  Bacteriostatic Antimicrobial Combination: Antagonistic Interaction between Epsilon-Viniferin and Vancomycin against Methicillin-Resistant Staphylococcus aureus 
BioMed Research International  2014;2014:461756.
Stilbenoids have been considered as an alternative phytotherapeutic treatment against methicillin-resistant Staphylococcus aureus (MRSA) infection. The combined effect of ε-viniferin and johorenol A with the standard antibiotics, vancomycin and linezolid, was assessed against MRSA ATCC 33591 and HUKM clinical isolate. The minimum inhibitory concentration (MIC) value of the individual tested compounds and the fractional inhibitory concentration index (FICI) value of the combined agents were, respectively, determined using microbroth dilution test and microdilution checkerboard (MDC) method. Only synergistic outcome from checkerboard test will be substantiated for its rate of bacterial killing using time-kill assay. The MIC value of ε-viniferin against ATCC 33591 and johorenol A against both strains was 0.05 mg/mL whereas HUKM strain was susceptible to 0.1 mg/mL of ε-viniferin. MDC study showed that only combination between ε-viniferin and vancomycin was synergistic against ATCC 33591 (FICI 0.25) and HUKM (FICI 0.19). All the other combinations (ε-viniferin-linezolid, johorenol A-vancomycin, and johorenol A-linezolid) were either indifferent or additive against both strains. However, despite the FICI value showing synergistic effect for ε-viniferin-vancomycin, TKA analysis displayed antagonistic interaction with bacteriostatic action against both strains. As conclusion, ε-viniferin can be considered as a bacteriostatic stilbenoid as it antagonized the bactericidal activity of vancomycin. These findings therefore disputed previous report that ε-viniferin acted in synergism with vancomycin but revealed that it targets similar site in close proximity to vancomycin's action, possibly at the bacterial membrane protein. Hence, this combination has a huge potential to be further studied and developed as an alternative treatment in combating MRSA in future.
doi:10.1155/2014/461756
PMCID: PMC3982270  PMID: 24783205
10.  Synergistic effects of Miconazole and Polymyxin B on microbial pathogens 
The therapeutic value of antibiotics depends on the susceptibility of the infecting microorganism and the pharmacological profile of the drugs. To assess the value of an antibiotic combination of polymyxin B and miconazole this study examined the in vitro synergistic potential of the two drugs on Gram-negative and Gram-positive bacteria and yeast. Antifungal and antibacterial activity was tested by minimum inhibitory concentration (MIC) of broth macrodilution and urea broth microdilution, by fluorescence microscopy and flow cytometry. Synergism was calculated using the fractional inhibitory concentration index (FICi). With Staphylococcus intermedius as target we found up to an eightfold reduction of the individual MICs when both drugs were combined. However, the FICi was 0.63 suggesting no real interaction between the two drugs. With Escherichia coli, Pseudomonas aeruginosa, and Malassezia pachydermatis as targets the antimicrobial drug combination reduced the MICs of polymyxin B and miconazole from fourfold to hundredfold resulting in FICi between 0.06 and 0.5 which defines a synergistic action. Thus, if polymyxin B and miconazole are combined their effect is greater than the sum of the effects observed with polymyxin B and miconazole independently, revealing bactericidal and fungicidal synergism. Our results indicate a strong therapeutic value for the combination of these antimicrobial agents against Gram-negative bacteria and yeast and a weaker value against Gram positive bacteria for clinical situations where these pathogens are involved.
doi:10.1007/s11259-008-9194-z
PMCID: PMC2707952  PMID: 19085068
Miconazole; Polymyxin; Antibiotic synergism; Otitis externa
11.  In vitro synergism of magnolol and honokiol in combination with antibacterial agents against clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) 
Background
Methicillin-resistant Staphylococcus aureus (MRSA) is a problematic pathogen posing a serious therapeutic challenge in the clinic. It is often multidrug-resistant (MDR) to conventional classes of antibacterial agents and there is an urgent need to develop new agents or strategies for treatment. Magnolol (ML) and honokiol (HL) are two naturally occurring diallylbiphenols which have been reported to show inhibition of MRSA. In this study their synergistic effects with antibacterial agents were further evaluated via checkerboard and time-kill assays.
Methods
The susceptibility spectrum of clinical MRSA strains was tested by the disk diffusion method. The minimal inhibitory concentrations (MICs) and minimal bactericidal concentrations (MBCs) of ML and HL were assayed by broth microdilution. The synergy was evaluated through checkerboard microdilution and time-killing experiments.
Results
ML and HL showed similar activity against both MSSA and MRSA with MIC/MBC at 16 ~ 64 mg/L, with potency similar to amikacin (AMK) and gentamicin (GEN). When they were used in combination with conventional antibacterial agents, they showed bacteriostatic synergy with FICIs between 0.25 ~ 0.5, leading to the combined MICs decreasing to as low as 1 ~ 2 and 1 ~ 16 mg/L for ML (HL) and the agents, respectively. MIC50 of the combinations decreased from 16 mg/L to 1 ~ 4 mg/L for ML (HL) and 8 ~ 128 mg/L to 2 ~ 64 mg/L for the antibacterial agents, which exhibited a broad spectrum of synergistic action with aminoglycosides (AMK, etilmicin (ETM) and GEN), floroquinolones (levofloxacin (LEV), ciprofloxacin and norfloxacin), fosfomycin (FOS) and piperacillin. The times of dilution (TOD, the extent of decreasing in MIC value) were determined up to 16 for the combined MIC. A more significant synergy after combining was determined as ML (HL) with AMK, ETM, GEN and FOS. ML (HL) combined with antibacterial agents did not show antagonistic effects on any of the ten MRSA strains. Reversal effects of MRSA resistance to AMK and GEN by ML and HL were also observed, respectively. All the combinations also showed better dynamic bactericidal activity against MRSA than any of single ML (HL) or the agents at 24 h incubation. The more significant synergy of combinations were determined as HL (ML) + ETM, HL + LEV and HL + AMK (GEN or FOS), with △LC24 of 2.02 ~ 2.25.
Conclusion
ML and HL showed synergistic potentiation of antibacterial agents against clinical isolates of MRSA and warrant further pharmacological investigation.
doi:10.1186/s12906-015-0938-3
PMCID: PMC4666064  PMID: 26627468
Magnolol; Honokiol; MRSA; Synergy; Antibacterial agent
12.  Nordihydroguaiaretic acid enhances the activities of aminoglycosides against methicillin- sensitive and resistant Staphylococcus aureus in vitro and in vivo 
Infections caused by methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA) are prevalent. MRSA infections are difficult to treat and there are no new classes of antibiotics produced to the market to treat infections caused by the resistant bacteria. Therefore, using antibiotic enhancers to rescue existing classes of antibiotics is an attractive strategy. Nordihydroguaiaretic acid (NDGA) is an antioxidant compound found in extracts from plant Larrea Tridentata. It exhibits antimicrobial activity and may target bacterial cell membrane. Combination efficacies of NDGA with many classes of antibiotics were examined by chequerboard method against 200 clinical isolates of MRSA and MSSA. NDGA in combination with gentamicin, neomycin, and tobramycin was examined by time-kill assays. The synergistic combinations of NDGA and aminoglycosides were tested in vivo using a murine skin infection model. Calculations of the fractional inhibitory concentration index (FICI) showed that NDGA when combined with gentamicin, neomycin, or tobramycin displayed synergistic activities in more than 97% of MSSA and MRSA, respectively. Time kill analysis demonstrated that NDGA significantly augmented the activities of these aminoglycosides against MRSA and MSSA in vitro and in murine skin infection model. The enhanced activity of NDGA resides on its ability to damage bacterial cell membrane leading to accumulation of the antibiotics inside bacterial cells. We demonstrated that NDGA strongly revived the therapeutic potencies of aminoglycosides in vitro and in vivo. This combinational strategy could contribute major clinical implications to treat antibiotic resistant bacterial infections.
doi:10.3389/fmicb.2015.01195
PMCID: PMC4621280  PMID: 26579101
nordihydroguaiaretic acid; gentamicin; neomycin; tobramycin; Staphylococcus aureus; antibiotic combination
13.  Antibacterial effects of Apis mellifera and stingless bees honeys on susceptible and resistant strains of Escherichia coli, Staphylococcus aureus and Klebsiella pneumoniae in Gondar, Northwest Ethiopia 
Background
Honey is a natural substance produced by honeybees and has nutritional and therapeutic uses. In Ethiopia, honeys are used traditionally to treat wounds, respiratory infections and diarrhoea. Recent increase of drug resistant bacteria against the existing antibiotics forced investigators to search for alternative natural remedies and evaluate their potential use on scientific bases. Thus, the aim of this study was to evaluate the antibacterial effects of different types of honeys in Ethiopia which are used traditionally to treat different types of respiratory and gastrointestinal infections.
Methods
Mueller Hinton agar (70191) diffusion and nutrient broth culture medium assays were performed to determine susceptibility of Staphylococcus aureus (ATCC 25923), Escherichia coli (ATCC 25922) and resistant clinical isolates (Methicillin resistant Staphylococcus aureus(MRSA), Escherichia coli(R) and Klebsiella pneumoniae (R), using honeys of Apis mellifera and stingless bees in northern and north western Ethiopia.
Results
Honey of the stingless bees produced the highest mean inhibition (22.27 ± 3.79 mm) compared to white honey (21.0 ± 2.7 mm) and yellow honey (18.0 ± 2.3 mm) at 50% (v/v) concentration on all the standard and resistant strains. Stingless bees honey was found to have Minimum Inhibitory Concentration (MIC) of 6.25% (6.25 mg/ml) for 80% of the test organisms compared to 40% for white and yellow Apis mellifera honeys. All the honeys were found to have minimum bactericidal concentration (MBC) of 12.5% (12.5 mg/ml) against all the test organisms. Staphylococcus aureus (ATCC 25923) was susceptible to amoxicillin, methicillin, kanamycine, tetracycline, and vancomycine standard antibiotic discs used for susceptibility tests. Similarly, Escherichia coli (ATCC 25922) was found susceptible for kanamycine, tetracycline and vancomycine. Escherichia coli (ATCC 25922) has not been tested for amoxicillin ampicillin and methicillin. The susceptibility tests performed against Staphylococcus aureus (MRSA), Escherichia coli (R) and Klebsiella pneumoniae (R) using three of methicillin, erythromycin, ampicillin, Penicillin and amoxicillin discs were resistant. But, these drug resistant strains were susceptible to antibacterial agents found in the honeys and inhibited from 16 mm to 20.33 mm.
Conclusions
Honeys in Ethiopia can be used as therapeutic agents for drug resistant bacteria after pharmaceutical standardization and clinical trials.
doi:10.1186/1472-6882-13-269
PMCID: PMC3817311  PMID: 24138782
Anticbacterial effects; Ethiopian honeys; Escherichia coli (ATCC 25922); Escherichia coli (R); Klebsiella pneumoniae (R); Staphylococcus aureus (ATCC 25923); Staphylococcus aureus (MRSA)
14.  Antibacterial activity of extracellular compounds produced by a Pseudomonas strain against methicillin-resistant Staphylococcus aureus (MRSA) strains 
Background
The emergence of multidrug-resistant bacteria is a world health problem. Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA) strains, is one of the most important human pathogens associated with hospital and community-acquired infections. The aim of this work was to evaluate the antibacterial activity of a Pseudomonas aeruginosa-derived compound against MRSA strains.
Methods
Thirty clinical MRSA strains were isolated, and three standard MRSA strains were evaluated. The extracellular compounds were purified by vacuum liquid chromatography. Evaluation of antibacterial activity was performed by agar diffusion technique, determination of the minimal inhibitory concentration, curve of growth and viability and scanning electron microscopy. Interaction of an extracellular compound with silver nanoparticle was studied to evaluate antibacterial effect.
Results
The F3 (ethyl acetate) and F3d (dichloromethane- ethyl acetate) fractions demonstrated antibacterial activity against the MRSA strains. Phenazine-1-carboxamide was identified and purified from the F3d fraction and demonstrated slight antibacterial activity against MRSA, and synergic effect when combined with silver nanoparticles produced by Fusarium oxysporum. Organohalogen compound was purified from this fraction showing high antibacterial effect. Using scanning electron microscopy, we show that the F3d fraction caused morphological changes to the cell wall of the MRSA strains.
Conclusions
These results suggest that P. aeruginosa-produced compounds such as phenazines have inhibitory effects against MRSA and may be a good alternative treatment to control infections caused by MRSA.
doi:10.1186/1476-0711-12-12
PMCID: PMC3695862  PMID: 23773484
Antibacterial activity; Methicillin-resistant; Pseudomonas aeruginosa; Staphylococcus aureus
15.  Evaluation of Combination Effects of Ethanolic Extract of Ziziphus mucronata Willd. subsp. mucronata Willd. and Antibiotics against Clinically Important Bacteria 
The Scientific World Journal  2013;2013:769594.
A pragmatic approach to the treatment of infectious diseases with multicausal agents and prevention of the development of resistant isolates is the combination of herbal remedies with the first-line antimicrobial agents to which most of them have become resistant. This study evaluated the interactions between the ethanolic bark extract of Ziziphus mucronata with known antimicrobial agents in vitro. In this study, the results showed that varied zones of inhibitions (ZME—chloramphenicol (17–42 mm), ZME—amoxicillin (17–35 mm), ZME—tetracycline (17–36 mm), ZME—ciprofloxacin (20–41 mm), ZME—nalidixic acid (17–34 mm), and ZME—kanamycin (17–38 mm)) were produced by the antibacterial combinations. At the highest combined concentrations, 12 isolates (ZME—ciprofloxacin) > 10 isolates (ZME—chloramphenicol) = (ZME—kanamycin) > 6 isolates (ZME—amoxicillin) = (ZME—nalidixic acid) and 5 isolates (ZME—tetracycline) were inhibited with zones of inhibition greater than 20 ± 1.0 mm. Although the agar diffusion assay suggested that the interactions between the ethanolic extract of Z. mucronata and the antibiotics were both synergistic and additive in nature, the fractional inhibitory concentration indices (FICI) showed that the interactions were synergistic (54.17%), additive (27.78%), indifferent (16.67%), and antagonistic (1.39%). While the fractional inhibitory concentration indices (FICIs) for synergism ranged between 0.00391 and 0.5, that of additivity ranged between 0.516 and 1.0, indifferences ranged between 1.062 and 3.0 and antagonistic interaction was 5.0. The synergistic effects implied that the antibacterial combinations would be more effective and useful in the treatment of multicausal and multidrug-resistant bacteria than a single monotherapy of either antibacterial agent.
doi:10.1155/2013/769594
PMCID: PMC3655675  PMID: 23737727
16.  Antibacterial activity of actinomycetes isolated from different soil samples of Sheopur (A city of central India) 
The main objective of the present study was isolation, purification, and characterization of actinomycetes from soil samples, having antimicrobial activity against 12 selected pathogenic strains. Soils samples were taken from different niche habitats of Sheopur district, Madhya Pradesh, India. These samples were serially diluted and plated on actinomycete isolation agar media. Potential colonies were screened, purified, and stored in glycerol stock. Isolates were morphologically and biochemically characterized. These isolates were subjected to extraction for production of the antibacterial compound. Antibacterial activity and Minimum Inhibitory Concentration (MIC) of the purified extract of isolates were evaluated. Totally 31 actinomycete isolates were tested for antagonistic activity against 12 pathogenic microorganisms. Isolates AS14, AS27, and AS28 were highly active, while AS1 showed less activity against the pathogenic microorganisms. Isolate AS7 exhibited the highest antagonistic activity against Bacillus cereus (24 mm) and AS16 showed the highest activity against Enterococcus faecalis (21 mm). MIC was also determined for actinomycete isolates against all the tested microorganisms. MIC of actinomycete isolates was found to be 2.5 mg/ml against Shigella dysenteriae, Vancomycin-resistant enterococci, and Klebsiella pneumoniae, and was 1.25 mg/ml for Staphylococcus saprophyticus, Streptococcus pyogenes, Staphylococcus epidermidis, Methicillin-resistant Staphylococcus, Bacillus cereus, Staphylococcus xylosus, Methicillin-resistant Staphylococcus aureus, Enterococcus faecalis, and Staphylococcus aureus. All actinomycetes isolates showed antibacterial activity against S. aureus, while they showed less activity against S. dysenteriae. These isolates had antibacterial activity and could be used in the development of new antibiotics for pharmaceutical or agricultural purposes.
doi:10.4103/2231-4040.111528
PMCID: PMC3696223  PMID: 23833752
Agar well diffusion method; antimicrobial activity; minimum inhibitory concentration; pathogenic microorganisms; Sheopur
17.  Enhancement of Neonatal Innate Defense: Effects of Adding an N-Terminal Recombinant Fragment of Bactericidal/Permeability-Increasing Protein on Growth and Tumor Necrosis Factor-Inducing Activity of Gram-Negative Bacteria Tested in Neonatal Cord Blood Ex Vivo 
Infection and Immunity  2000;68(9):5120-5125.
Innate defense against microbial infection requires the action of neutrophils, which have cytoplasmic granules replete with antibiotic proteins and peptides. Bactericidal/permeability-increasing protein (BPI) is found in the primary granules of adult neutrophils, has a high affinity for lipopolysaccharides (or “endotoxins”), and exerts selective cytotoxic, antiendotoxic, and opsonic activity against gram-negative bacteria. We have previously reported that neutrophils derived from newborn cord blood are deficient in BPI (O. Levy et al., Pediatrics 104:1327–1333, 1999). The relative deficiency in BPI of newborns raised the possibility that supplementing the levels of BPI in plasma might enhance newborn antibacterial defense. Here we determined the effects of addition of recombinant 21-kDa N-terminal BPI fragment (rBPI21) on the growth and tumor necrosis factor (TNF)-inducing activity of representative gram-negative clinical isolates. Bacteria were tested in citrated newborn cord blood or adult peripheral blood. Bacterial viability was assessed by plating assay, and TNF-α release was measured by enzyme-linked immunosorbent assay. Whereas adult blood limited the growth of all isolates except Klebsiella pneumoniae, cord blood also allowed logarithmic growth of Escherichia coli K1/r and Citrobacter koseri. Bacteria varied in their susceptibility to rBPI21's bactericidal action: E. coli K1/r was relatively susceptible (50% inhibitory concentration [IC50], ∼10 nM), C. koseri was intermediate (IC50, ∼1,000 nM), Klebsiella pneumoniae was resistant (IC50, ∼10,000 nM), and Enterobacter cloacae and Serratia marcescens were highly resistant (IC50, >10,000 nM). All isolates were potent inducers of TNF-α activity in both adult and newborn cord blood. In contrast to its variable antibacterial activity, rBPI21 consistently inhibited the TNF-inducing activity of all strains tested (IC50, 1 to 1,000 nM). The antibacterial effects of rBPI21 were additive with those of a combination of conventional antibiotics typically used to treat bacteremic newborns (ampicillin and gentamicin). Whereas ampicillin and gentamicin demonstrated little inhibition of bacterially induced TNF release, addition of rBPI21 either alone or together with ampicillin and gentamicin profoundly inhibited release of this cytokine. Thus, supplementing newborn cord blood with rBPI21 potently inhibited the TNF-inducing activity of a variety of gram-negative bacterial clinical pathogens and, in some cases, enhanced bactericidal activity. These results suggest that administration of rBPI21 may be of clinical benefit to neonates suffering from gram-negative bacterial infection and/or endotoxemia.
PMCID: PMC101753  PMID: 10948134
18.  Antibacterial activities of the methanol extracts of seven Cameroonian dietary plants against bacteria expressing MDR phenotypes 
SpringerPlus  2013;2:363.
The morbidity and mortality caused by bacterial infections significantly increased with resistance to commonly used antibiotics. This is partially due to the activation of efflux pumps in Gram-negative bacteria. The present work designed to assess the in vitro antibacterial activities of seven Cameroonian dietary plants (Sesamum indicum, Sesamum radiatum, Cinnamomum zeylanicum, Corchous olitorius, Cyperus esculentus, Adansonia digitata, Aframomum kayserianum), against multidrug resistant (MDR) Gram-negative bacteria over expressing active efflux pumps. The standard phytochemical methods were used to detect the main classes of secondary metabolites in the extracts. The antibacterial activities of the studied extracts in the absence or presence of an efflux pump inhibitor (PAβN) were evaluated using liquid microbroth dilution method. The results obtained indicated that apart from the extract of C. esculentus, all other samples contained alkaloids, phenols and polyphenols meanwhile other classes of chemicals were selectively present. The studied extracts displayed antibacterial activities with minimal inhibitory concentrations (MICs) values ranged from 64 to 1024 μg/mL on the majority of the 27 tested microbial strains. The extract of S. indicum was active against 77.77% of the tested microorganisms whilst the lowest MIC value (64 μg/mL) was recorded with that of A. kayserianum against E. aerogenes EA294. The results of the present work provide baseline information on the possible used of the tested Cameroonian dietary plants in the treatment of bacterial infections including multi-drug resistant phenotypes.
doi:10.1186/2193-1801-2-363
PMCID: PMC3738912  PMID: 23961425
Antibacterial activity; Cameroon; Dietary plants; Efflux pumps; Gram-negative bacteria; Multi-drug resistant
19.  Antimicrobial activity of polyphenol-rich fractions from Sida alba L. (Malvaceae) against co-trimoxazol-resistant bacteria strains 
Background
The increased resistance of microorganisms to the currently used antimicrobials has lead to the evaluation of other agents that might have antimicrobial activity. Medicinal plants are sources of phytochemicals which are able to initiate different biological activities including antimicrobials
Materials and methods
In vitro antibacterial (MIC, MBC and time-kill studies) of polyphenol-rich fractions from Sida alba L. (Malvaceae) was assessed using ten bacteria strains (Gram-negative and Gram-positive).
Results
All test bacteria were susceptible to the polyphenol-rich fractions. Time-kill results showed that after 5 h exposition there was no viable microorganism in the initial inoculum and the effect of polyphenol-rich fractions was faster on Enterococcus faecalis (Gram-positive bacterium) comparatively to the other bacteria strains.
Conclusion
The data analysis indicates that the tested of polyphenol-rich fractions has significant effects when compared with the standard antibiotic. These results therefore justify the traditional use of sida alba L., alone or in combination with other herbs to treat bacterial infections.
doi:10.1186/1476-0711-11-5
PMCID: PMC3316130  PMID: 22364123
20.  In vitro synergy testing of novel antimicrobial combination therapies against Neisseria gonorrhoeae 
Background
Antimicrobial-resistant Neisseria gonorrhoeae is a major public health threat. Current CDC treatment guidelines for uncomplicated gonorrhoea recommend only ceftriaxone plus either azithromycin or doxycycline. Additional treatment options are needed.
Methods
We used antibiotic gradient synergy testing (the Etest) to evaluate antimicrobial combinations that included a third-generation cephalosporin (cefixime or ceftriaxone) plus azithromycin, doxycycline, gentamicin, rifampicin or fosfomycin. We tested each combination against 28 clinical N. gonorrhoeae isolates and four control strains of varying susceptibility profiles, and compared the results with those obtained using combination antimicrobial testing using agar dilution. We calculated the fractional inhibitory concentration index (FICI) for each combination to determine synergy, the results being interpreted as follows: FICI ≤ 0.5 = synergy; FICI > 4.0 = antagonism; and FICI > 0.5–4 = indifference.
Results
The combinations of a third-generation cephalosporin plus azithromycin, doxycycline, rifampicin, gentamicin or fosfomycin produced FICIs of indifference. The Etest and agar dilution methods produced comparable results.
Conclusions
Combinations of ceftriaxone plus rifampicin, gentamicin or fosfomycin may warrant further clinical investigation as treatments for gonorrhoea. Using the Etest for synergy testing is a viable method that has practical advantages over agar dilution.
doi:10.1093/jac/dkt540
PMCID: PMC4019328  PMID: 24468865
antimicrobial resistance; sexually transmitted diseases; novel therapies
21.  In vitro Antibacterial Activity of Aqueous and Ethanol Extracts of Aristolochia indica and Toddalia asiatica Against Multidrug-Resistant Bacteria 
Bacteria have developed multidrug resistance against available antimicrobial agents. Infectious diseases caused by these multidrug-resistant bacteria are major causes of morbidity and mortality in human beings. Synthetic drugs are expensive and inadequate for the treatment of diseases, causing side effects and ineffective against multidrug-resistant bacteria. The medicinal plants are promising to have effective antimicrobial property due to presence of phytochemical compounds like alkaloids, flavanoids, tannins and phenolic compounds. The present study aimed to find the antimicrobial activity of medicinal plants against multidrug-resistant bacteria. Multidrug-resistant bacteria were identified by Kirby-Bauer disc diffusion method. Production of β-lactamases (extended spectrum β-lactamases, metallo β-lactamase and AmpC β-lactamase) were identified by combination disc method. Antibacterial activity of aqueous and ethanol extract of Aristolochia indica and Toddalia asiatica were detected by agar well diffusion assay and minimum inhibitory concentration. All bacteria used in this study showed antibiotic resistance to ≥3 antibiotics. Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Proteus mirabilis and Vibrio cholerae were found to be positive for β-lactamase production. Ethanol extract of Aristolochia indica showed more significant antibacterial activity against multidrug-resistant bacteria than Toddalia asiatica. Ethanol extracts of Aristolochia indica and Toddalia asiatica showed minimum inhibitory concentration values of 50-100 μg/ml and 100-200 μg/ml, respectively against multidrug-resistant bacteria. From this study, it was concluded that Aristolochia indica has more potential to treat multidrug-resistant bacteria than Toddalia asiatica.
doi:10.4103/0250-474X.174991
PMCID: PMC4778242  PMID: 26997710
Multidrug-resistant bacteria; combination disc method; Aristolochia indica; Toddalia asiatica; minimum inhibitory concentration; extended spectrum β-lactamases
22.  Antimicrobial Effects and Resistant Regulation of Magnolol and Honokiol on Methicillin-Resistant Staphylococcus aureus 
BioMed Research International  2015;2015:283630.
The antimicrobial killing activity toward methicillin-resistant Staphylococcus aureus (MRSA) has been a serious emerging global issue. In a continuing search for compounds with antibacterial activity against several microorganisms including S. aureus and MRSA, an n-hexane extract of Magnolia officinalis was found to contain magnolol. This compound exhibited potent activity against S. aureus, standard methicillin-susceptible S. aureus (MSSA), and MRSA as well as clinical MRSA isolates. When combined with oxacillin, the antibacterial activities of magnolol and honokiol against the MRSA strain were increased compared to single treatment without antibiotics at 10 µg/mL and 25 µg/mL, respectively. These activities of magnolol and honokiol were dose dependent. Also, magnolol showed synergistic effects with oxacillin against 13 clinical isolates of MRSA. It was determined that magnolol and honokiol had a synergistic effect with oxacillin against MRSA strain. Furthermore, the magnolol inhibited the expression of the resistant genes, mecA, mecI, femA, and femB, in mRNA. We concluded that the antibacterial activity of magnolol against MRSA strain is more related to the mecI's pathway and components of the cell wall than mecR1. Therefore, the results obtained in this study suggest that the combination of magnolol and antibiotics could lead to the development of new combination antibiotics against MRSA infection.
doi:10.1155/2015/283630
PMCID: PMC4556871  PMID: 26357651
23.  In vitro activity of monoclonal and recombinant yeast killer toxin-like antibodies against antibiotic-resistant gram-positive cocci. 
Molecular Medicine  2000;6(7):613-619.
BACKGROUND: Monoclonal (mAbKT) and recombinant single-chain (scFvKT) anti-idiotypic antibodies were produced to represent the internal image of a yeast killer toxin (KT) characterized by a wide spectrum of antimicrobial activity, including gram-positive cocci. Pathogenic eukaryotic and prokaryotic microorganisms, such as Candida albicans, Pneumocystis carinii, and a multidrug-resistant strain of Mycobacterium tuberculosis, presenting specific, although yet undefined, KT-cell wall receptors (KTR), have proven to be killed in vitro by mAbKT and scFvKT. mAbKT and scFvKT exert a therapeutic effect in vivo in experimental models of candidiasis and pneumocystosis by mimicking the functional activity of protective antibodies naturally produced in humans against KTR of infecting microorganisms. The swelling tide of concern over increasing bacterial resistance to antibiotic drugs gives the impetus to develop new therapeutic compounds against microbial threat. Thus, the in vitro bactericidal activity of mAbKT and scFvKT against gram-positive, drug-resistant cocci of major epidemiological interest was investigated. MATERIALS AND METHODS: mAbKT and scFvKT generated by hybridoma and DNA recombinant technology from the spleen lymphocytes of mice immunized with a KT-neutralizing monoclonal antibody (mAb KT4) were used in a conventional colony forming unit (CFU) assay to determine, from a qualitative point of view, their bactericidal activity against Staphylococcus aureus, S. haemolyticus, Enterococcus faecalis, E. faecium, and Streptococcus pneumoniae strains. These bacterial strains are characterized by different patterns of resistance to antibiotics, including methicillin, vancomycin, and penicillin. RESULTS: According to the experimental conditions adopted, no bacterial isolate proved to be resistant to the activity of mAbKT and scFvKT. CONCLUSIONS: scFvKT exerted a microbicidal activity against multidrug resistant bacteria, which may represent the basis for the drug modeling of new antibiotics with broad antibacterial spectra to tackle the emergence of microbial resistance.
PMCID: PMC1949971  PMID: 10997342
24.  Use of Pharmacodynamic Parameters To Predict Efficacy of Combination Therapy by Using Fractional Inhibitory Concentration Kinetics 
Combination therapy with antimicrobial agents can be used against bacteria that have reduced susceptibilities to single agents. We studied various tobramycin and ceftazidime dosing regimens against four resistant Pseudomonas aeruginosa strains in an in vitro pharmacokinetic model to determine the usability of combination therapy for the treatment of infections due to resistant bacterial strains. For the selection of an optimal dosing regimen it is necessary to determine which pharmacodynamic parameter best predicts efficacy during combination therapy and to find a simple method for susceptibility testing. An easy-to-use, previously described E-test method was evaluated as a test for susceptibility to combination therapy. That test resulted in a MICcombi, which is the MIC of, for example, tobramycin in the presence of ceftazidime. By dividing the tobramycin and ceftazidime concentration by the MICcombi at each time point during the dosing interval, fractional inhibitory concentration (FIC) curves were constructed, and from these curves new pharmacodynamic parameters for combination therapy were calculated (i.e., AUCcombi, Cmax-combi, T>MIC-combi, and T>FICi, where AUCcombi, Cmax-combi, T>MIC-combi, and T>FICi are the area under the FICcombi curve, the peak concentration of FICcombi, the time that the concentration of the combination is above the MICcombi, and the time above the FIC index, respectively). By stepwise multilinear regression analysis, the pharmacodynamic parameter T>FICi proved to be the best predictor of therapeutic efficacy during combination therapy with tobramycin and ceftazidime (R2 = 0.6821; P < 0.01). We conclude that for combination therapy with tobramycin and ceftazidime the T>FICi is the parameter best predictive of efficacy and that the E-test for susceptibility testing of combination therapy gives promising results. These new pharmacodynamic parameters for combination therapy promise to provide better insight into the rationale behind combination therapy.
PMCID: PMC105535  PMID: 9559776
25.  Graphene oxide-silver nanocomposite as a promising biocidal agent against methicillin-resistant Staphylococcus aureus 
Background
Methicillin-resistant Staphylococcus aureus (MRSA) has been responsible for serious hospital infections worldwide. Nanomaterials are an alternative to conventional antibiotic compounds, because bacteria are unlikely to develop microbial resistance against nanomaterials. In the past decade, graphene oxide (GO) has emerged as a material that is often used to support and stabilize silver nanoparticles (AgNPs) for the preparation of novel antibacterial nanocomposites. In this work, we report the synthesis of the graphene-oxide silver nanocomposite (GO-Ag) and its antibacterial activity against relevant microorganisms in medicine.
Materials and methods
GO-Ag nanocomposite was synthesized through the reduction of silver ions (Ag+) by sodium citrate in an aqueous GO dispersion, and was extensively characterized using ultraviolet-visible absorption spectroscopy, X-ray diffraction, thermogravimetric analysis, X-ray photoelectron spectroscopy, and transmission electron microscopy. The antibacterial activity was evaluated by microdilution assays and time-kill experiments. The morphology of bacterial cells treated with GO-Ag was investigated via transmission electron microscopy.
Results
AgNPs were well distributed throughout GO sheets, with an average size of 9.4±2.8 nm. The GO-Ag nanocomposite exhibited an excellent antibacterial activity against methicillin-resistant S. aureus, Acinetobacter baumannii, Enterococcus faecalis, and Escherichia coli. All (100%) MRSA cells were inactivated after 4 hours of exposure to GO-Ag sheets. In addition, no toxicity was found for either pristine GO or bare AgNPs within the tested concentration range. Transmission electronic microscopy images offered insights into how GO-Ag nanosheets interacted with bacterial cells.
Conclusion
Our results indicate that the GO-Ag nanocomposite is a promising antibacterial agent against common nosocomial bacteria, particularly antibiotic-resistant MRSA. Morphological injuries on MRSA cells revealed a likely loss of viability as a result of the direct contact between bacteria and the GO-Ag sheets.
doi:10.2147/IJN.S90660
PMCID: PMC4636171  PMID: 26586946
graphene oxide; silver nanoparticles; graphene oxide-silver nanocomposite; antibacterial agent; MRSA; Escherichia coli

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