Inhibition of the ATP Synthase Eliminates the Intrinsic Resistance of Staphylococcus aureus towards Polymyxins

Abstract

Staphylococcus aureus is intrinsically resistant to polymyxins (polymyxin B and colistin), an important class of cationic antimicrobial peptides used in treatment of Gram-negative bacterial infections. To understand the mechanisms underlying intrinsic polymyxin resistance in S. aureus, we screened the Nebraska Transposon Mutant Library established in S. aureus strain JE2 for increased susceptibility to polymyxin B. Nineteen mutants displayed at least 2-fold reductions in MIC, while the greatest reductions (8-fold) were observed for mutants with inactivation of either graS, graR, vraF, or vraG or the subunits of the ATP synthase (atpA, atpB, atpG, or atpH), which during respiration is the main source of energy. Inactivation of atpA also conferred hypersusceptibility to colistin and the aminoglycoside gentamicin, whereas susceptibilities to nisin, gallidermin, bacitracin, vancomycin, ciprofloxacin, linezolid, daptomycin, and oxacillin were unchanged. ATP synthase activity is known to be inhibited by oligomycin A, and the presence of this compound increased polymyxin B-mediated killing of S. aureus. Our results demonstrate that the ATP synthase contributes to intrinsic resistance of S. aureus towards polymyxins and that inhibition of the ATP synthase sensitizes S. aureus to this group of compounds. These findings show that by modulation of bacterial metabolism, new classes of antibiotics may show efficacy against pathogens towards which they were previously considered inapplicable. In light of the need for new treatment options for infections with serious pathogens like S. aureus, this approach may pave the way for novel applications of existing antibiotics.

Monocyte metabolic reprogramming promotes pro-inflammatory activity and Staphylococcus aureus biofilm clearance

“…Furthermore, oligomycin delivery by direct intra-articular injection into the infected joint in either one bolus or two sequential doses also had no effect on bacterial burden (S8B Fig). Oligomycin also lacked bactericidal activity against S. aureus across a range of concentrations during planktonic growth, early biofilm formation, and mature biofilm in vitro (S9 Fig), in agreement with prior reports demonstrating that oligomycin alone does not affect S. aureus growth [41,42]. To rule out the possibility that oligomycin altered S. aureus metabolism to make organisms more susceptible to immune-mediated clearance, metabolomics was performed.…”

Interventions on Metabolism: Making Antibiotic-Susceptible Bacteria

“…If an organism is intrinsically resistant to a given antibiotic, the drug is useless for treating infections with this microorganism. The recent publication of an article by Martin Vestergaard et al, “Inhibition of the ATP synthase eliminates the intrinsic resistance of Staphylococcus aureus towards polymyxins,” together with some other previous works on metabolic interventions, challenges this paradigm ( 1 ). From a chemical point of view, an antibiotic is active if it reaches its target at a sufficient concentration for inhibition of target function or activity.…”

Inactivation of Glutamine Synthetase-Coding Gene glnA Increases Susceptibility to Quinolones Through Increasing Outer Membrane Protein F in Salmonella enterica Serovar Typhi

“…The internal concentration of glutamine is the main intracellular signal for regulating nitrogen availability in enteric bacteria (Zimmer et al, 2000;Switzer et al, 2018). Nitrogen is essential for the biosynthesis of macromolecules in bacteria; thus, the adaptive response to metabolic stress induced by starvation of nitrogen (as it is the case of glutamine auxotrophic bacteria) could affect bacterial physiology, including the susceptibility to antimicrobials which today is known to be modulated by metabolism (Maria-Neto et al, 2012;Peng et al, 2015;Vestergaard et al, 2017;Cui et al, 2019).…”