Unveiling the physiological mechanisms that drive the emergence of antibiotic resisters from antibiotic persister population of mycobacteria

Abstract

The physiological mechanisms behind the emergence of antibiotic-resistant bacteria from their antibiotic-persister population are beginning to be explored. Here we delineate the sequential physiological events that drive the emergence of rifampin-resistant rpoB mutants from rifampin-persister population of mycobacteria during prolonged exposure. The rifampin-persister population generated elevated levels of hydroxyl radical, which inflicted mutations, enabling regrowth of the persister cells to form multi-septated, multi-nucleated elongated cells. These cells, through multiple divisions, produced multiple sister-daughter cells, causing an abrupt, unexpectedly high increase of rifampin-resistant colonies. Similar response was observed against moxifloxacin also. Earlier studies on the rifampin/moxifloxacin-exposed laboratory/clinical M. tuberculosis strains from in-vitro cultures and infected mouse-lung also showed cfu spurt, but went unnoticed/unreported. It is likely that these sequential physiological events may be driving the emergence of antibiotic-resistant tubercle bacilli in TB patients also. Escherichia coli also has been found to respond similarly against subminimal inhibitory concentrations of ciprofloxacin. Thus, the present findings attain broad significance as a general physiological mechanism used by diverse bacterial genera to emerge as drug-resistant strains against antibiotics.