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1.  Targeted antimicrobial activity of a specific IgG–SMAP28 conjugate against Porphyromonas gingivalis in a mixed culture 
Antimicrobial peptides coupled to a ligand, receptor or antibody for a specific pathogenic bacteria could be used to develop narrow-spectrum pharmaceuticals with ‘targeted’ antimicrobial activity void of adverse reactions often associated with the use of broad-spectrum antibiotics. To assess the feasibility of this approach, in this study sheep myeloid antimicrobial peptide (SMAP) 28 was linked to affinity- and protein G-purified rabbit immunoglobulin G (IgG) antibodies specific to the outer surface of Porphyromonas gingivalis strain 381. The selective activity of the P. gingivalis IgG–SMAP28 conjugate was then assessed by adding it to an artificially generated microbial community containing P. gingivalis, Aggregatibacter actinomycetemcomitans and Peptostreptococcus micros. The specificity of the P. gingivalis IgG–SMAP28 conjugate in this mixed culture was concentration-dependent. The conjugate at 50 μg protein/mL lacked specificity and killed P. gingivalis, A. actinomycetemcomitans and P. micros. The conjugate at 20 μg protein/mL was more specific and killed P. gingivalis. This is an initial step to develop a selective antimicrobial agent that can eliminate a specific periodontal pathogen, such as P. gingivalis, from patients with periodontal disease without harming the normal commensal flora.
doi:10.1016/j.ijantimicag.2008.05.021
PMCID: PMC3169388  PMID: 18778918
Porphyromonas gingivalis; Aggregatibacter actinomycetemcomitans; Peptostreptococcus micros; Cathelicidins; Targeted antimicrobial activity; SMAP28
2.  Pharmacodynamic activity of the lantibiotic MU1140 
This study evaluated the pharmacodynamics of the lantibiotic MU1140 and the ability of selected organisms to develop resistance to this antibiotic. MU1140 demonstrated activity against all Gram-positive organisms tested, including oxacillin- and vancomycin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecalis (VREF). No activity was observed against Gram-negative bacteria or yeast. Time–kill studies revealed that MU1140 was rapidly bactericidal against Streptococcus pneumoniae and multidrug-resistant S. aureus, whilst it was bacteriostatic against VREF. In vitro resistance development to MU1140, tested by sequential subculturing in subinhibitory concentrations of MU1140, revealed a stable three-fold increase in the minimum inhibitory concentration (MIC) for S. aureus and S. pneumoniae. Subsequent subculturing of the strains with elevated MICs in antibiotic-free media for 7 days did not result in a reduction of their MIC values for MU1140. Collectively, our findings illustrate the therapeutic potential of MU1140 for management of Gram-positive infections.
doi:10.1016/j.ijantimicag.2008.07.028
PMCID: PMC2643042  PMID: 18835136
Lantibiotic; MU1140; Lanthionine; Pharmacodynamics; Antibiotic resistance; MRSA; VRE
3.  ksgA mutations confer resistance to kasugamycin in Neisseria gonorrhoeae 
The aminoglycoside antibiotic kasugamycin (KSG) inhibits translation initiation and thus the growth of many bacteria. In this study, we tested the susceptibilities to KSG of 22 low-passage clinical isolates and 2 laboratory strains of Neisseria gonorrhoeae. Although the range of KSG minimum inhibitory concentrations (MICs) was narrow (seven-fold), clinical isolates and laboratory strains fell into three distinct classes of KSG sensitivity, susceptible, somewhat sensitive and resistant, with MICs of 30, 60–100 and 200 μg/mL, respectively. Two genes have previously been shown to be involved in bacterial KSG resistance: rpsI, which encodes the 30S ribosomal subunit S9 protein; and ksgA, which encodes a predicted dimethyltransferase. Although sequencing of rpsI and ksgA from clinical isolates revealed polymorphisms, none correlated with the MICs of KSG. Ten spontaneous KSG-resistant (KSGR) mutants were isolated from laboratory strain FA1090 at a frequency of <4.4 × 10−6 resistant colony-forming units (CFU)/total CFU. All isolated KSGR variants had mutations in ksgA, whilst no mutations were observed in rpsI. ksgA mutations conferring KSG resistance included four point mutations, two in-frame and one out-of-frame deletions, one in-frame duplication and two frame-shift insertions. These data show a narrow range of susceptibilities for the clinical isolates and laboratory strains examined; moreover, the differences in MICs do not correlate with nucleotide polymorphisms in rpsI or ksgA. Additionally, spontaneous KSGR mutants arise by a variety of ksgA mutations.
doi:10.1016/j.ijantimicag.2008.08.030
PMCID: PMC2723803  PMID: 19097863
Mutagenesis; Gonorrhoea; Antibiotic resistance
4.  Differential pathogenesis of cowpox virus intranasal infections in mice induced by low and high inoculum volumes and effects of cidofovir treatment 
The causes of death from intranasal cowpox virus infections in mice remain unclear. Hypotheses include severe pneumonitis, hepatitis, and/or hyperproduction of cytokines and chemokines. This work explores these hypotheses by studying the influence of low and high volume virus inoculums on viral pathogenesis. BALB/c mice were infected intranasally with a syncytium-forming variant of cowpox virus in 5-μl or 50-μl volumes containing the same infectious virus challenge dose. The 50-μl infection produced a more rapidly lethal disease associated with severe pneumonitis, high lung and nasal virus titers, and increases in cytokine and chemokine levels in lungs and nasal tissue, while liver infection was minimal. The 5-μl inoculum infection was also lethal, but the infection was primarily confined to the upper respiratory tract, and included elevated nasal cytokine and chemokine levels. The pro-inflammatory cytokine, interleukin-6, was particularly high in both infections. Treatment of the infections with cidofovir (100 mg/kg/day for 2 days starting 24 h after virus exposure) led to survival and suppression of tissue virus titers. Treatment reduced pneumonitis in the 50-μl infection, and lessened cytokine hyperproduction in both infections. We conclude that 5-μl volume inoculum of cowpox virus causes a lethal upper respiratory tract infection, while the 50-μl inoculum targets both upper and lower respiratory tracts, with excessive release of systemic pro-inflammatory factors occurring. Cidofovir effectively treated both infections and slowed viral replication sufficiently to subdue the exaggerated release of pro-inflammatory mediators.
doi:10.1016/j.ijantimicag.2007.11.013
PMCID: PMC2367113  PMID: 18206353
orthopoxvirus; cowpox; antiviral; cidofovir; cytokines; chemokines
5.  Treatment of chronic prostatitis/chronic pelvic pain syndrome 
International journal of antimicrobial agents  2008;31(Supplement 1):112-116.
Acceptance of the National Institutes of Health definition of Category III Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) and the development and validation of the Chronic Prostatitis Symptom Index has stimulated significant research into treatment of this condition. Evidence-based suggestions for treatment include the following. (i) Antimicrobials cannot be recommended for men with longstanding, previously treated CP/CPPS. (ii) Alpha-blockers can be recommended as first-line medical therapy, particularly in alpha-blocker-naïve men with moderately severe symptoms who have relatively recent onset of symptoms. (iii) Alpha-blockers cannot be recommended in men with longstanding CP/CPPS who have tried and failed alpha-blockers in the past. And (iv) anti-inflammatory therapy, finasteride and pentosan polysulfate are not recommended as primary treatment; however, they may have a useful adjunctive role in a multimodal therapeutic regimen. Early data on herbal therapies, particularly quercetin and cernilton, are intriguing, but larger multicentre, randomised, placebo-controlled trials are required before a high level of evidence recommendation can be made on its use. At this time, surgery (including minimally invasive) is recommended only for definitive indications and not generally for CP/CPPS.
doi:10.1016/j.ijantimicag.2007.07.028
PMCID: PMC2245867  PMID: 17954024
Prostatitis; Chronic pelvic pain syndrome; Treatment
6.  A pharmacokinetic/pharmacodynamic mathematical model accurately describes the activity of voriconazole against Candida spp. in vitro 
We developed a pharmacokinetic/pharmacodynamic (PK/PD) mathematical model that fits voriconazole time–kill data against Candida isolates in vitro and used the model to simulate the expected kill curves for typical intravenous and oral dosing regimens. A series of Emax mathematical models were used to fit time–kill data for two isolates each of Candida albicans, Candida glabrata and Candida parapsilosis. PK parameters extracted from human data sets were used in the model to simulate kill curves for each isolate. Time–kill data were best fit by using an adapted sigmoidal Emax model that corrected for delays in candidal growth and the onset of voriconazole activity, saturation of the number of Candida and the steepness of the concentration–response curve. The rates of maximal killing by voriconazole (kmax) were highly correlated with the growth rates (ks) of the isolates (Pearson’s correlation coefficient = 0.9861). Simulations using PK parameters derived from the human data sets showed fungistatic effects against each of the isolates. In conclusion, we demonstrated that the activity of voriconazole against Candida isolates can be accurately described using a mathematical model. In the future, it might be possible to devise optimal dosing regimens of voriconazole using the model and PK data collected in vivo.
doi:10.1016/j.ijantimicag.2007.11.015
PMCID: PMC2367122  PMID: 18215509
Candida spp; Voriconazole; Time-kill assay; Mathematical modelling

Results 1-6 (6)