A combined, chemical-microbiology approach to understand the function of novel antibiotic resistance determinant in Gram-negative bacteria.

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An ongoing collaboration between King's College London and Public Health England has recently identified a class of regulator proteins that may play an important role in mediating intrinsic resistance, via direct binding to particular types of antibiotic, in the important Gram-negative pathogen Klebsiella pneumoniae. We have now identified two unrelated chemical entities, but with a shared molecular target (DNA-gyrase), for which resistance appears to be mediated by this regulator. This raises the possibility that this protein is either a multidrug binding domain, capable of binding and responding to a wide range of antibiotics or is able to functionally mimic the gyrase-binding pocket. Both of these possibilities are intriguing, and we plan to use a combination of homology modelling and chemical synthesis, coupled with molecular microbiology techniques to provide tools to unpick the mechanism of action of these proteins. This family of proteins is widely distributed across a range of Gram-negative pathogens and with, some modifications to predicted domain structure, in Gram-positive pathogens also. They are also found in a number of bacteria clustered with polyketide synthase or non-ribosomal peptide synthases, where they may act as immunity proteins with, as yet, unidentified compounds. This may represent a pool of resistance determinants that impact on intrinsic susceptibility to existing and novel antibiotics. It may also represent a series of affinity ligands to be used in vitro or in vivo, that could be used to identify and characterise novel antimicrobial compounds from a variety of sources.