Site-selective modifications by lipid A phosphoethanolamine transferases linked to colistin resistance and bacterial fitness

Rising levels of resistance to increasing numbers of antimicrobials have led to the revival of last resort antibiotic colistin. Unfortunately, resistance to colistin is also spreading in the form of <i>mcr</i> genes, making it essential to (i) improve the identification of resistant bacteria to allow clinicians to prescribe effective drug regimens and (ii) develop new combination therapies effective at targeting resistant bacteria. Our results demonstrate that PETs, including MCR variants, are site-selective in <i>Escherichia coli</i> and that site-selectivity correlates with the level of susceptibility and fitness costs conferred by certain PETs. Site selectivity associated with a given PET may not only help predict colistin resistance phenotypes but may also provide an avenue to (i) improve drug regimens and (ii) develop new combination therapies to better combat colistin-resistant bacteria.