Antimicrobial drugs provide a front-line defense against pathogenic infections, however their effectiveness is continually threatened by the evolution of microbial resistance mechanisms. Over the past two decades, the number of pathogens that are resistant to one or multiple forms of antimicrobials has surged, resulting in the common circulation of drug-resistant mutants, such as methicillin resistant Staphylococcus aureus (MRSA), multi- and extensively-drug resistant Mycobacterium tuberculosis (MDR-/XDR-TB), and Gram-negative Acinetobacter species. Our group has recently identified several salicylanilides with antibacterial activity against Mycobacterium strains, S. aureus and MRSA. In addition to antibacterial activity, these compounds exhibited potency in the biochemical inhibition of bacterial transglycosylase (TGase), which is a key enzyme of bacterial cell-wall biosynthesis. Targeting TGase has several advantages: it is conserved among many pathogenic bacteria, it does not have human counterparts, and, most importantly, TGase is less prone to acquisition of drug-resistance. Using available structural information and results of modeling experiments we have performed a structure-activity relationship study, and identified key features that are required for the inhibition of TGase (Figure 1). Many of these compounds have potent MIC values in M. smegmatis, a model organism for tuberculosis infection.

Structure optimization of small molecule inhibitors of bacterial transglycosylase

251st National Meeting (2016)

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