Unveiling the role of a periplasmic lipocalin and a membrane cytochrome in antibiotic heteroresistance of Gram-negative bacteria

The knowledge gap–Treating infections by Gram-negative bacteria is becoming increasingly difficult since these bacteria often show intrinsic high-level resistance to virtually all clinically approved antibiotics. Compounding this problem, many bacteria display heteroresistance, a phenomenon where subpopulations of seemingly isogenic bacteria exhibit a range of susceptibilities to a particular antibiotic, resulting in ineffective microbial killing. Bacterial exposure to sublethal antibiotic concentrations elicit adaptive bacterial stress responses, enhancing antibiotic resistance and tolerance. Our research has revealed that these adaptive responses occur against bactericidal antibiotics, irrespective of their chemical nature. We have discovered that under conditions of bactericidal stress bacteria hyperproduce a lipocalin and its associated cytochrome (BcnA/LcoA), and polyamines, all of which contribute to increased antibiotic resistance and heteroresistance. A major stressor resulting from antibiotic action, is membrane-lipid peroxidation, which destroys lipids in the bacterial membrane eliciting adaptive bacterial responses that result in even higher antibiotic resistance. Therefore, elucidating the fundamental biological question of how the double-membraned Gram-negatives protect their outer membranes from lipid peroxidation may reveal novel ways to overcome resistance and heteroresistance.
Our discovery–Our research supported by BBSRC BB/S006281/1, recently published in PlosBiology, described a hitherto unknown evolutionary conserved peroxidation detoxification system that protects the bacterial cell envelope from lipid peroxidation and plays a key role in intrinsic resistance against multiple classes of antibiotics. This system comprises three proteins which are conserved in all Gram-negative bacteria: the BcnA lipocalin (putative scavenger of lipid peroxyl radicals), the LcoA membrane cytochrome-b561, and PsrA, a cytoplasmic aldehyde reductase. New...