Identifying the Biosynthetic Origins of Nybomycin, a Reverse Antibiotic

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This project will investigate the biosynthesis of nybomycin, a Streptomyces natural product. Nybomycin is a molecule of unique chemical structure and highly unusual biological activity. It was first reported in 1955 [1] and while it was found to have useful antibacterial potency, it was also shown to be extremely insoluble in water and did not find clinical utility. It was rediscovered in 2012 [2] during a screen for substances active against multidrug-resistant Staphylococcus aureus M50 (MRSA) and it was found to have a curious activity profile: nybomycin was inactive against strains carrying intact gyrase genes (quinolone sensitive) and active against those with mutated gyrase genes (quinolone resistant). Unexpectedly, rather than select for further additional mutations to generate dual resistance, quinolone resistant strains treated with nybomycin reverted to quinolone sensitivity by reversion of the relevant mutation. This means that any bacteria that develop resistance to nybomycin will revert to being sensitive to quinolone antibiotics, potentially bypassing the usual cycle of endless accumulation of antibiotic resistances. Theoretically, the efficacy of quinolone antibiotics can be preserved by sequential application of nybomycin and quinolone antibiotics. Due to these phenomena nybomycin was deemed to be the first of a novel group termed 'reverse antibiotics'.
The aim of this research project is to identify the nybomycin biosynthetic genes using comparative transcriptional analysis and/or transposon mutagenesis. Inspection of the chemical structure in conjunction with preliminary stable isotope feeding data from the 1970s [3-5] suggest that nybomycin biosynthesis does not conform to any general, known biosynthetic pathway and likely comprises novel chemical and biochemical mechanisms. In our hands, typical genome mining techniques (antiSMASH 3.0 and MultiGeneBlast) have failed to identify the biosynthetic gene cluster (BGC), providing further support to the notion that the biosynthetic pathway is unique. Thus, we will be applying novel methodology towards the identification of an unprecedented BGC thereby enabling the understanding of a novel biosynthetic pathway that will involve new chemistry and enzymology.

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