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1.  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.
PMCID: PMC3349319  PMID: 22619603
2.  Evaluation of the Combined Effects of Stilbenoid from Shorea gibbosa and Vancomycin against Methicillin-Resistant Staphylococcus aureus (MRSA) 
Pharmaceuticals  2012;5(9):1032-1043.
The aim of this study is to determine the combined effects of stilbenoids from Shorea gibbosa and vancomycin against methicillin-resistant Staphylococcus aureus (MRSA). A total of nine pure compounds, five stilbenoid dimers ε-viniferin, ampelopsin A, balanocarpol, laevifonol and diptoindonesin G and four stilbenoid trimers α-viniferin, johorenol A, ampelopsin E and vaticanol G were evaluated for their antibacterial activities against ATCC 33591 and a HUKM clinical isolate. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) for each active compound were determined using the serial microdilution and plate-streak techniques. The combined effect of stilbenoids with vancomycin against MRSA was evaluated using the checkerboard assay to determine their fractional inhibitory concentration (FIC) index values. The MIC value of α-viniferin on both MRSA strains was 100 μg/mL, whereas those of johorenol A on ATCC 33591 and HUKM strain were 100 μg/mL and 200 μg/mL, respectively. The MIC values of ampelopsin E and vaticanol G were higher than 400 μg/mL. Out of the five stilbenoid dimers, only ε-viniferin was capable of inhibiting the growth of both MRSA strains at MIC 400 μg/mL. The MBC value of ε-viniferin, α-viniferin and johorenol A showed bacteriostatic action against MRSA. The FIC index value of ε-viniferin and α-viniferin in combination with vancomycin showed an additive effect (0.5 < FIC ≤ 2.0) against both MRSA strains. Johorenol A-vancomycin combination was also additive against HUKM strain, but it showed synergistic interaction with vancomycin against ATCC 33591 (FIC < 0.5). Stilbenoid compounds from Shorea gibbosa have anti-MRSA activity and huge potential as an alternative phytotherapy in combating MRSA infections.
PMCID: PMC3816650  PMID: 24280704
Shorea gibbosa; FIC; stilbenoid; bacteriostatic activity; additivity; MRSA
3.  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.
PMCID: PMC3430230  PMID: 22942699
anti-MRSA activity; Hypericum japonicum; Isojacareubin; MIC; synergy
4.  Anti-nociceptive properties in rodents and the possibility of using polyphenol-rich fractions from sida urens L. (Malvaceae) against of dental caries bacteria 
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.
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.
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.
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.
PMCID: PMC3699430  PMID: 23787152
5.  In vitro antibacterial activity of combinations of fosfomycin, minocycline and polymyxin B on pan-drug-resistant Acinetobacter baumannii 
The aim of this study was to determine the effects of combinations of fosfomycin, minocycline and polymyxin B in the treatment of pan-drug-resistant Acinetobacter baumannii (PDR-Ab). The in vitro antibacterial activities of the drugs were evaluated by determination of the minimum inhibitory concentration (MIC) and the fractional inhibitory concentration index (FICI). A total of 25 strains of PDR-Ab were selected using the VITEK32 microbial analysis instrument and the Kirby-Bauer (K-B) method. A broth microdilution method was used to determine the MIC for each of the three drugs, and the checkerboard method was simultaneously used to determine the MICs for combinations of the drugs. FICI values were also calculated. While fosfomycin alone was ineffective for the treatment of PDR-Ab, its MIC value was significantly reduced when used in combination with minocycline or polymyxin B. The combined use of minocycline and polymyxin B also significantly reduced the MIC value of each drug. The FICI values revealed that the drugs had synergistic or additive effects when used in combination. The determination of the MIC and FICI values for the combinations of drugs demonstrated that there is synergistic or additive effect upon the combined use of fosfomycin with minocycline or polymyxin B. The combined use of minocycline and polymyxin B also results in a significant reduction in the MIC values of the two drugs. These experimental results may provide a basis for the future clinical treatment of Acinetobacter baumannii.
PMCID: PMC3702694  PMID: 23837064
pan-drug resistant Acinetobacter baumannii; minocycline; fosfomycin; polymyxin B; minimum inhibitory concentration; fractional inhibitory concentration index
6.  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.
PMCID: PMC2707952  PMID: 19085068
Miconazole; Polymyxin; Antibiotic synergism; Otitis externa
7.  Antibacterial activity of extracellular compounds produced by a Pseudomonas strain against methicillin-resistant Staphylococcus aureus (MRSA) strains 
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.
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.
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.
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.
PMCID: PMC3695862  PMID: 23773484
Antibacterial activity; Methicillin-resistant; Pseudomonas aeruginosa; Staphylococcus aureus
8.  Synergistic antimicrobial activity between pentacyclic triterpenoids and antibiotics against Staphylococcus aureus strains 
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%.
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.
PMCID: PMC3127748  PMID: 21658242
9.  Comparative Study of the In Vitro Antibacterial Activity of Cefoxitin, Cefuroxime, and Cephaloridine 
The in vitro antibacterial effects of cefoxitin, a semisynthetic cephamycin, cefuroxime, a new cephalosporin antibiotic, and cephaloridine were compared. With gram-positive bacteria, marked differences were found only in the effects against Streptococcus faecalis, where cephaloridine and cefuroxime were superior to cefoxitin. With gram-negative aerobic bacteria, cefoxitin, which is known to be more resistant to beta-lactamases from gram-negative bacteria than any cephalosporin, was found to be more effective than cefuroxime and cephaloridine against ampicillin-resistant strains of Escherichia coli and indole-positive strains of Proteus. Haemophilus influenzae was found to be more susceptible to cefuroxime than to cefoxitin and cephaloridine. When ampicillin-resistant strains of H. influenzae were tested, markedly higher minimal inhibitory concentration values were obtained with cephaloridine in comparison to those obtained with ampicillin-susceptible strains. These increases in the minimal inhibitory concentration values were not observed with cefoxitin and cefuroxime, probably due to the resistance of these two compounds to beta-lactamases. Strains of Bacteroides fragilis were found to be much more susceptible to cefoxitin than to cefuroxime, which in turn was superior to cephaloridine. The results obtained indicate that cefoxitin and cefuroxime both are superior in their antibacterial spectra to the cephalosporins that are now in clinical use.
PMCID: PMC429561  PMID: 1259406
10.  Cefuroxime, a New Cephalosporin Antibiotic: Activity In Vitro 
Cefuroxime is a new broad-spectrum cephalosporin antibiotic with increased stability to β-lactamases. This stability, although no absolute in all cases, has the effect of widening the antibacterial spectrum of the compound so that many organisms resistant to the established cephalosporins are susceptible to cefuroxime. It is active against gram-positive organisms, including penicillinase-producing staphylococci, but it is less active against methicillin-resistant strains. In addition to its high activity against non-β-lactamase-producing gram-negative bacteria, cefuroxime effectively inhibits the growth of many β-lactamase-producing strains, including Enterobacter, Klebsiella, and indole-positive Proteus spp. It is highly active against Neisseria gonorrhoeae, Neisseria meningitidis, and also Haemophilus influenzae, including ampicillin-resistant strains. Cefuroxime is rapidly bactericidal and induces the formation and subsequent lysis of filamentous forms over a small concentration range.
PMCID: PMC429562  PMID: 1259407
11.  Antibacterial Activity of Extracts of Acacia Aroma Against Methicillin-Resistant And Methicillin-Sensitive Staphylococcus 
Brazilian Journal of Microbiology  2010;41(3):581-587.
Antibacterial activity of organic and aqueous extracts of Acacia aroma was evaluated against methicillin-resistant Staphylococcus aureus (MRSA), methicillin sensitive Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus epidermidis. Inhibition of bacterial growth was determined using agar diffusion and bioautographic methods. Among all assayed organic extracts only ethanolic and ethyl acetate extracts presented highest activities against all tested Staphylococcus strains with minimal inhibitory concentration (MIC) values ranging from 2.5 to 10 mg/ml and from 2.5 to 5 mg/ml respectively. The aqueous extracts show little antibacterial activity against Staphylococcus strains. The bioautography assay demonstrated well-defined growth inhibition zones against S. aureus in correspondence with flavonoids and saponins. A. aroma would be an interesting topic for further study and possibly for an alternative treatment for skin infections.
PMCID: PMC3768637  PMID: 24031532
Acacia aroma; Antibacterial activity; Staphylococcus; Tusca
12.  In Vitro and In Vivo Properties of Ro 63-9141, a Novel Broad-Spectrum Cephalosporin with Activity against Methicillin-Resistant Staphylococci 
Ro 63-9141 is a new member of the pyrrolidinone-3-ylidenemethyl cephem series of cephalosporins. Its antibacterial spectrum was evaluated against significant gram-positive and gram-negative pathogens in comparison with those of reference drugs, including cefotaxime, cefepime, meropenem, and ciprofloxacin. Ro 63-9141 showed high antibacterial in vitro activity against gram-positive bacteria except ampicillin-resistant enterococci, particularly vancomycin-resistant strains of Enterococcus faecium. Its MIC at which 90% of the isolates tested were inhibited (MIC90) for methicillin-resistant Staphylococcus aureus (MRSA) was 4 μg/ml. Ro 63-9141 was bactericidal against MRSA. Development of resistance to the new compound in MRSA was not observed. Ro 63-9141 was more potent than cefotaxime against penicillin-resistant Streptococcus pneumoniae (MIC90 = 2 μg/ml). It was active against ceftazidime-susceptible strains of Pseudomonas aeruginosa and against Enterobacteriaceae except Proteus vulgaris and some isolates producing extended-spectrum β-lactamases. The basis for the antibacterial spectrum of Ro 63-9141 lies in its affinity to essential penicillin-binding proteins, including PBP 2′ of MRSA, and its stability towards β-lactamases. The in vivo findings were in accordance with the in vitro susceptibilities of the pathogens. These data suggest the potential utility of Ro 63-9141 for the therapy of infections caused by susceptible pathogens, including MRSA. Since insufficient solubility of Ro 63-9141 itself precludes parenteral administration in humans, a water-soluble prodrug, Ro 65-5788, is considered for development.
PMCID: PMC90381  PMID: 11181368
13.  Antibacterial Activity of 2-(2′,4′-Dibromophenoxy)-4,6-dibromophenol from Dysidea granulosa 
Marine Drugs  2009;7(3):464-471.
2-(2′,4′-Dibromophenoxy)-4,6-dibromophenol isolated from the marine sponge Dysidea granulosa (Bergquist) collected off the coast of Lakshadweep islands, Indian Ocean, exhibited potent and broad spectrum in-vitro antibacterial activity, especially against methicillin resistant Staphylococcus aureus (MRSA), methicillin sensitive Staphylococcus aureus (MSSA), vancomycin resistant Enterococci (VRE), vancomycin sensitive Enterococci (VSE) and Bacillus spp. Minimal inhibitory concentration (MIC) was evaluated against 57 clinical and standard strains of Gram positive and Gram negative bacteria. The observed MIC range was 0.117–2.5 μg/mL against all the Gram positive bacteria and 0.5–2 μg/mL against Gram negative bacteria. The in-vitro antibacterial activity observed was better than that of the standard antibiotic linezolid, a marketed anti-MRSA drug. The results establish 2-(2′,4′-dibromophenoxy)-4,6-dibromophenol, as a potential lead molecule for anti-MRSA and anti-VRE drug development.
PMCID: PMC2763112  PMID: 19841726
Dysidea granulosa; 2-(2′,4′-dibromophenoxy)-4,6-dibromophenol; antibacterial activity; methicillin resistant Staphylococcus aureus; vancomycin resistant enterococci
14.  Activity of the Novel Peptide Arminin against Multiresistant Human Pathogens Shows the Considerable Potential of Phylogenetically Ancient Organisms as Drug Sources▿  
Antimicrobial Agents and Chemotherapy  2009;53(12):5245-5250.
The emergence of multidrug-resistant bacteria highlights the need for new antibacterial agents. Arminin 1a is a novel antimicrobial peptide discovered during investigations of the epithelial defense of the ancient metazoan Hydra. Following proteolytic processing, the 31-amino-acid-long positively charged C-terminal part of arminin 1a exhibits potent and broad-spectrum activity against bacteria, including multiresistant human pathogenic strains, such as methicillin-resistant Staphylococcus aureus (MRSA) strains (minimal bactericidal concentration, 0.4 μM to 0.8 μM). Ultrastructural observations indicate that bacteria are killed by disruption of the bacterial cell wall. Remarkably, the antibacterial activity of arminin 1a is not affected under the physiological salt conditions of human blood. In addition, arminin 1a is a selective antibacterial agent that does not affect human erythrocyte membranes. Arminin 1a shows no sequence homology to any known antimicrobial peptide. Because of its high level of activity against multiresistant bacterial strains pathogenic for humans, the peptide arminin 1a is a promising template for a new class of antibiotics. Our data suggest that ancient metazoan organisms such as Hydra hold promise for the detection of novel antimicrobial molecules and the treatment of infections caused by multiresistant bacteria.
PMCID: PMC2786370  PMID: 19770277
15.  In Vitro Activity of Telavancin in Combination with Colistin versus Gram-Negative Bacterial Pathogens 
The treatment of Gram-negative infections is increasingly compromised by the spread of resistance. With few agents currently in development, clinicians are now considering the use of unorthodox combination therapies for multidrug-resistant strains. Here we assessed the in vitro activity of the novel lipoglycopeptide telavancin (TLV) when combined with colistin (COL) versus 13 Gram-negative type strains and 66 clinical isolates. Marked synergy was observed in either checkerboard (fractional inhibitory concentration index [FICI], <0.5; susceptibility breakpoint index [SBPI], >2) or time-kill assays (>2-log reduction in viable counts compared with starting inocula at 24 h) versus the majority of COL-susceptible enterobacteria, Stenotrophomonas maltophilia, and Acinetobacter baumannii isolates, but only limited effects were seen against Pseudomonas aeruginosa or strains with COL resistance. Using an Etest/agar dilution method, the activity of TLV was potentiated by relatively low concentrations of COL (0.25 to 0.75 μg/ml), reducing the MIC of TLV from >32 μg/ml to ≤1 μg/ml for 35% of the clinical isolates. This provides further evidence that glycopeptide-polymyxin combinations may be a useful therapeutic option in the treatment of Gram-negative infections.
PMCID: PMC3370780  PMID: 22491686
16.  Antibacterial activity of cefmetazole alone and in combination with fosfomycin against methicillin- and cephem-resistant Staphylococcus aureus. 
In vitro and in vivo antibacterial activities of cefmetazole alone and in combination with fosfomycin against methicillin- and cephem-resistant (MR) strains of Staphylococcus aureus were investigated, and the mechanism of synergistic effect between cefmetazole and fosfomycin was also studied. Cefmetazole inhibited the growth of 71 strains of MR S. aureus at concentrations ranging from 1.56 to 50 micrograms/ml; the antibacterial activity of cefmetazole against these strains was enhanced approximately 4 times with the addition of fosfomycin at a concentration of 1.56 micrograms/ml. The binding affinity of cefmetazole for the penicillin-binding protein 2' fraction specific for MR S. aureus was higher than that of methicillin, cloxacillin, cefazolin, and cefotaxime. A synergy experiment in vitro was performed by checkerboard titration with Mueller-Hinton agar plates containing various concentrations and ratios of cefmetazole and fosfomycin. The fractional inhibitory concentration index ranged from 0.09 to 0.75. Exposure of cefmetazole plus fosfomycin to exponentially growing cultures at a concentration at which both antibiotics had no bactericidal effect when given alone exerted bactericidal action. Combined administration of cefmetazole with fosfomycin at a ratio of 1:1 against systemic MR S. aureus infections with mice showed an excellent therapeutic efficacy as compared with administration of either antibiotic alone. Penicillin-binding protein 2', 2, and 4 fractions were scarcely detectable in MR S. aureus strains grown in the presence of fosfomycin at concentrations of 0.25 MIC and 0.5 MIC, respectively.
PMCID: PMC180619  PMID: 3468883
17.  Combined antibacterial activity of amoxicillin with clavulanic acid against ampicillin-resistant strains. 
Strains of bacteria resistant to beta-lactam antibiotics have been increasing in number and are becoming troublesome in clinical medicine. The in vitro antibacterial activity of amoxicillin combined with clavulanic acid was determined on selected ampicillin-resistant clinical isolates. Synergistic effects were produced by amoxicillin with clavulanic acid against ampicillin-resistant strains of Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris, and Bacteroides fragilis. Inhibition of the beta-lactamases produced by the ampicillin-resistant strains was confirmed, especially against the penicillinases mediated by the R factor and the cephalosporinases produced by P.vulgaris and B. fragilis. The inhibitory effect of clavulanic acid against beta-lactamases was irreversible because of the high affinity of clavulanic acid to the enzymes.
PMCID: PMC283901  PMID: 6967713
18.  RWJ-54428 (MC-02,479), a New Cephalosporin with High Affinity for Penicillin-Binding Proteins, Including PBP 2a, and Stability to Staphylococcal Beta-Lactamases 
RWJ-54428 (MC-02,479) is a new cephalosporin active against gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). The potency of this new cephalosporin against MRSA is related to a high affinity for penicillin-binding protein 2a (PBP 2a), as assessed in a competition assay using biotinylated ampicillin as the reporter molecule. RWJ-54428 had high activity against MRSA strains COL and 67-0 (MIC of 1 μg/ml) and also showed affinity for PBP 2a, with a 50% inhibitory concentration (IC50) of 0.7 μg/ml. RWJ-54428 also displayed excellent affinity for PBP 5 from Enterococcus hirae R40, with an IC50 of 0.8 μg/ml and a MIC of 0.5 μg/ml. The affinity of RWJ-54428 for PBPs of β-lactam-susceptible S. aureus (MSSA), enterococci (E. hirae), and Streptococcus pneumoniae showed that the good affinity of RWJ-54428 for MRSA PBP 2a and E. hirae PBP 5 does not compromise its binding to susceptible PBPs. RWJ-54428 showed stability to hydrolysis by purified type A β-lactamase isolated from S. aureus PC1. In addition, RWJ-54428 displayed low MICs against strains of S. aureus bearing the four classes of staphylococcal β-lactamases, including β-lactamase hyperproducers. The frequency of isolation of resistant mutants to RWJ-54428 from MRSA strains was very low. In summary, RWJ-54428 has high affinity to multiple PBPs and is stable to β-lactamase, properties that may explain our inability to find resistance by standard methods. These data are consistent with its excellent activity against β-lactam-resistant gram-positive bacteria.
PMCID: PMC151748  PMID: 12543674
19.  In Vitro and In Vivo Profiles of ACH-702, an Isothiazoloquinolone, against Bacterial Pathogens▿ 
ACH-702, a novel isothiazoloquinolone (ITQ), was assessed for antibacterial activity against a panel of Gram-positive and Gram-negative clinical isolates and found to possess broad-spectrum activity, especially against antibiotic-resistant Gram-positive strains, including methicillin-resistant Staphylococcus aureus (MRSA). For Gram-negative bacteria, ACH-702 showed exceptional potency against Haemophilus influenzae, Moraxella catarrhalis, and a Neisseria sp. but was less active against members of the Enterobacteriaceae. Good antibacterial activity was also evident against several anaerobes as well as Legionella pneumophila and Mycoplasma pneumoniae. Excellent bactericidal activity was observed for ACH-702 against several bacterial pathogens in time-kill assays, and postantibiotic effects (PAEs) of >1 h were evident with both laboratory and clinical strains of staphylococci at 10× MIC and similar in most cases to those observed for moxifloxacin at the same MIC multiple. In vivo efficacy was demonstrated against S. aureus with murine sepsis and thigh infection models, with decreases in the number of CFU/thigh equal to or greater than those observed after vancomycin treatment. Macromolecular synthesis assays showed specific dose-dependent inhibition of DNA replication in staphylococci, and biochemical analyses indicated potent dual inhibition of two essential DNA replication enzymes: DNA gyrase and topoisomerase IV. Additional biological data in support of an effective dual targeting mechanism of action include the following: low MIC values (≤0.25 μg/ml) against staphylococcal strains with single mutations in both gyrA and grlA (parC), retention of good antibacterial activity (MICs of ≤0.5 μg/ml) against staphylococcal strains with two mutations in both gyrA and grlA, and low frequencies for the selection of higher-level resistance (<10−10). These promising initial data support further study of isothiazoloquinolones as potential clinical candidates.
PMCID: PMC3101440  PMID: 21464250
20.  In Vitro and In Vivo Antibacterial Activities of CS-023 (RO4908463), a Novel Parenteral Carbapenem 
CS-023 (RO4908463, formerly R-115685) is a novel 1β-methylcarbapenem with 5-substituted pyrrolidin-3-ylthio groups, including an amidine moiety at the C-2 position. Its antibacterial activity was tested against 1,214 clinical isolates of 32 species and was compared with those of imipenem, meropenem, ceftazidime, ceftriaxone, ampicillin, amikacin, and levofloxacin. CS-023 exhibited a broad spectrum of activity against gram-positive and -negative aerobes and anaerobes, including methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis, penicillin-resistant Streptococcus pneumoniae (PRSP), β-lactamase-negative ampicillin-resistant Haemophilus influenzae, and Pseudomonas aeruginosa. CS-023 showed the most potent activity among the compounds tested against P. aeruginosa and MRSA, with MICs at which 90% of isolates tested were inhibited of 4 μg/ml and 8 μg/ml, respectively. CS-023 was stable against hydrolysis by the β-lactamases from Enterobacter cloacae and Proteus vulgaris. CS-023 also showed potent activity against extended-spectrum β-lactamase-producing Escherichia coli. The in vivo efficacy of CS-023 was evaluated with a murine systemic infection model induced by 13 strains of gram-positive and -negative pathogens and a lung infection model induced by 2 strains of PRSP (serotypes 6 and 19). Against the systemic infections with PRSP, MRSA, and P. aeruginosa and the lung infections, the efficacy of CS-023 was comparable to those of imipenem/cilastatin and vancomycin (tested against lung infections only) and superior to those of meropenem, ceftriaxone, and ceftazidime (tested against P. aeruginosa infections only). These results suggest that CS-023 has potential for the treatment of nosocomial bacterial infections by gram-positive and -negative pathogens, including MRSA and P. aeruginosa.
PMCID: PMC1196225  PMID: 16048932
21.  Proteome Analyses of Cellular Proteins in Methicillin-Resistant Staphylococcus aureus Treated with Rhodomyrtone, a Novel Antibiotic Candidate 
PLoS ONE  2011;6(2):e16628.
The ethanolic extract from Rhodomyrtus tomentosa leaf exhibited good antibacterial activities against both methicillin-resistant Staphylococcus aureus (MRSA) and S. aureus ATCC 29213. Its minimal inhibitory concentration (MIC) values ranged from 31.25–62.5 µg/ml, and the minimal bactericidal concentration (MBC) was 250 µg/ml. Rhodomyrtone, an acylphloroglucinol derivative, was 62.5–125 times more potent at inhibiting the bacteria than the ethanolic extract, the MIC and MBC values were 0.5 µg/ml and 2 µg/ml, respectively. To provide insights into antibacterial mechanisms involved, the effects of rhodomyrtone on cellular protein expression of MRSA have been investigated using proteomic approaches. Proteome analyses revealed that rhodomyrtone at subinhibitory concentration (0.174 µg/ml) affected the expression of several major functional classes of whole cell proteins in MRSA. The identified proteins involve in cell wall biosynthesis and cell division, protein degradation, stress response and oxidative stress, cell surface antigen and virulence factor, and various metabolic pathways such as amino acid, carbohydrate, energy, lipid, and nucleotide metabolism. Transmission electron micrographs confirmed the effects of rhodomyrtone on morphological and ultrastructural alterations in the treated bacterial cells. Biological processes in cell wall biosynthesis and cell division were interrupted. Prominent changes including alterations in cell wall, abnormal septum formation, cellular disintegration, and cell lysis were observed. Unusual size and shape of staphylococcal cells were obviously noted in the treated MRSA. These pioneer findings on proteomic profiling and phenotypic features of rhodomyrtone-treated MRSA may resolve its antimicrobial mechanisms which could lead to the development of a new effective regimen for the treatment of MRSA infections.
PMCID: PMC3033880  PMID: 21326597
22.  CP-45,899 in combination with penicillin or ampicillin against penicillin-resistant Staphylococcus, Haemophilus influenzae, and Bacteroides. 
CP-45,899 is a new, semisynthetic beta-lactamase inhibitor. When tested alone, CP-45,899 displayed only weak antibacterial activity, with the notable exception of its potent action against penicillin-susceptible and -resistant Neisseria gonorrhoeae. A combination of 3.12 microgram of CP-45,899 per ml with 3.12 microgram of ampicillin per ml, tested in broth cultures, inhibited ca. 90% of resistant Staphylococcus and Haemophilus influenzae strains; similar data were obtained in a variety of media. The same combination of CP-45,899 with ampicillin or penicillin G inhibited 90% of Bacteroides fragilis as interpreted from agar dilution minimal inhibitory concentrations. Inhibitory concentrations of CP-45,899-ampicillin were bactericidal against H. influenzae strains and were as bactericidal as nafcillin or cephalothin against S. aureus. Ampicillin-resistant S. aureus, H. influenzae, and B. fragilis strains did not develop resistance to CP-45,899-ampicillin when transferred as many as six passages in the presence of a sublethal concentration of the combination.
PMCID: PMC283841  PMID: 6249192
23.  In Vitro Activities of Linezolid Combined with Other Antimicrobial Agents against Staphylococci, Enterococci, Pneumococci, and Selected Gram-Negative Organisms 
The activities of linezolid, an oxazolidinone antibacterial agent active against gram-positive organisms, alone and in combination with 35 antimicrobial agents were tested in vitro against methicillin-sensitive (n = 1 to 2 strains) and methicillin-resistant (n = 8 to 10) Staphylococcus aureus strains; vancomycin-sensitive (n = 6) and vancomycin-resistant (n = 6 to 8) Enterococcus faecalis strains; vancomycin-sensitive (n = 5) and vancomycin-resistant (n = 6) Enterococcus faecium strains; penicillin-sensitive (n = 2 to 5), penicillin-intermediate (n = 5 to 6), and penicillin-resistant (n = 5 to 6) Streptococcus pneumoniae strains; Escherichia coli (n = 6); and Klebsiella pneumoniae (n = 6). The fractional inhibitory concentration indices of linezolid in combination with other antimicrobial agents for the organisms tested were generated on checkerboard broth microdilution plates prepared by a semiautomated method. Of 1,380 organism-drug combinations, 1,369 (99.2%) combinations of linezolid with 28 antimicrobial drugs were indifferent, 9 combinations (0.65%) of linezolid with 6 drugs (amoxicillin, erythromycin, imipenem, sparfloxacin, teicoplanin, and tetracycline) were synergistic, and 2 combinations (0.15%) of linezolid with 2 drugs (ofloxacin and sparfloxacin) were antagonistic. Overall, the in vitro data demonstrated that linezolid combined with other antimicrobial agents primarily produces an indifferent response, with infrequent occurrences of synergism and antagonism.
PMCID: PMC155858  PMID: 12760865
24.  Alafosfalin, a new inhibitor of cell wall biosynthesis: in vitro activity against urinary isolates in Japan and potentiation with beta-lactams. 
A new phosphonopeptide, alafosfalin, was evaluated for in vitro antibacterial activity and for synergism with beta-lactams, using 475 Japanese clinical isolates from urinary tract infections. Alafosfalin was found to be highly active against Escherichia coli and moderately active against Serratia, Klebsiella, Enterobacter, and Citrobacter, but less active against gram-positive organisms than were beta-lactams such as cephazolin or ampicillin and inactive against indole-positive Proteus, Pseudomonas, and Acinetobacter. Potentiation with the two beta-lactams (fractional inhibitory concentration less than or equal to 0.5) was found in 10 to 40% of susceptible strains in 4:1 and 1:4 combinations, and to a lesser extent in those species or genera that were insensitive to alafosfalin alone. No cross resistance was seen between alafosfalin and the beta-lactams or any other commonly used antibacterial agents tested. Effect on selected ampicillin-resistant strains, differential sensitivity to alafosfalin among resistant strains of various types, and sensitivity of alafosfalin-insensitive E. coli and Klebsiella to other antibiotics are also discussed.
PMCID: PMC352880  PMID: 518073
25.  Evaluation of Antimicrobial Activity of the Methanol Extracts from 8 Traditional Medicinal Plants 
Toxicological Research  2011;27(1):31-36.
The methanol extract of 12 medicinal plants were evaluated for its antibacterial activity against Gram-positive (5 strains) and Gram-negative bacteria (10 strains) by assay for minimum inhibitory concentration (MIC) and minimum bacterial concentration (MBC) . The antibacterial activity was determined by an agar dilution method (according to the guidelines of Clinical and Laboratory Standard Institute) . All the compounds (12 extracts) of the 8 medicinal plants (leaf or root) were active against both Gram-negative and Gram-positive bacteria. Gram-negative showed a more potent action than Gram positive bacteria. The MIC concentrations were various ranged from 0.6 μg/ml to 5000 μg/ml. The lowest MIC (0.6 μg/ml) and MBC (1.22 μg/ml) values were obtained with extract on 4 and 3 of the 15 microorganisms tested, respectively.
PMCID: PMC3834511  PMID: 24278548
Antimicrobial activity; traditional medicinal plants; minimum inhibitory concentration (MIC) ; minimum bacterial concentration (MBC) ; methanol extract; agar dilution method .

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