In our study, isolates resembling PFGE type EMRSA-16 harboured more biocide resistance genes than other types. The observed reduction in susceptibility of clinical isolates to chlorhexidine may mean that a selective pressure is being exerted by residues in the clinical environment, and highlights the importance of efficacy testing on clinical strains and good infection control practices. The development of reduced microbial susceptibility to biocides represents a serious cause for concern in the clinical environment.

Pulsed-field gel electrophoresis (PFGE) was used to investigate the dissemination and diversity of ampicillin-resistant (Amp r ) and nalidixic acid-resistant (Nal r ) commensal Escherichia coli strains in a cohort of 48 newborn calves. Calves were sampled weekly from birth for up to 21 weeks and a single resistant isolate selected from positive samples for genotyping and further phenotypic characterization. The Amp r population showed the greatest diversity, with a total of 56 different genotype patterns identified, of which 5 predominated, while the Nal r population appeared to be largely clonal, with over 97% of isolates belonging to just two different PFGE patterns. Distinct temporal trends were identified in the distribution of several Amp r genotypes across the cohort, with certain patterns predominating at different points in the study. Cumulative recognition of new Amp r genotypes within the cohort was biphasic, with a turning point coinciding with the housing of the cohort midway through the study, suggesting that colonizing strains were from an environmental source on the farm. Multiply resistant isolates dominated the collection, with >95% of isolates showing resistance to at least two additional antimicrobials. Carriage of resistance to streptomycin, sulfamethoxazole, and tetracycline was the most common combination, found across several different genotypes, suggesting the possible spread of a common resistance element across multiple strains. The proportion of Amp r isolates carrying sulfamethoxazole resistance increased significantly over the study period (P < 0.05), coinciding with a decline in the most common genotype pattern. These data indicate that calves were colonized by a succession of multiply resistant strains, with a probable environmental source, that disseminated through the cohort over time.

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Background:The past decade has been a lean period for the discovery of antibiotics with very few approvals of new antibacterial agents by FDA. However, emergence of Multi Drug Resistant organisms (MDRO) and Extensively Drug Resistant organisms (XDRO) pathogens have led to increased attention to this field. Center for Disease Control and Prevention (CDC) has declared infections caused by MDR ESKAPE pathogens as a critical area of unmet medical need. Further, FDA has also announced various incentives to support the Infectious Diseases Society of America (IDSA) aspiration to develop 10 new antibiotics by 2020. In this presentation, I will discuss challenges in the discovery of antibacterial compounds with a case study of Leucine tRNA synthetase inhibitor (LRSI).Methods & Materials: Various properties of antibacterial standard of care agents analyzed with respect to physicochemical, safety and activity against MDROs/XDROs. Also, merits and demerits of novel targets vs. novel approaches were considered. In order to explore novel targets we have designed, synthesized & profiled novel LRSI. The profile of our compound was compared with reported LRSI to identify the differentials.Results: Unlike general drugs, antibacterial compounds need distinct physicochemical properties in order to work efficiently in different cellular milieu of host & pathogen. Safety (selectivity & toxicity) is critical as doses required to control the infection are usually high. New compounds should not only be effective against MDROs but also possess lower risk of resistance development and relapse. We have identified novel selective Leucine tRNA synthetase inhibitor (LRSI) for Gram negative MDROs. On analysis this compound shows distinct advantages over previously reported inhibitor.Conclusion: To circumvent the challenges in the discovery of antibacterial compounds, the Pharma industry recognizes the need of novel targets and approaches to tackle the ever evolving pathogens. Towards this pursuit we identified a novel Leucine tRNA synthetase inhibitor (LRSI) with potent activity against MDROs. Promising profile of this novel inhibitor merits further development for clinical use.