Glucose-Induced Cyclic Lipopeptides Resistance in Bacteria via ATP Maintenance through Enhanced Glycolysis

Abstract

SummaryCyclic lipopeptide (CLP) antibiotics have a mechanism that causes membrane malfunction. Thus mechanisms of bacterial resistance to CLPs are thought to modify cell surfaces. However, we found that bacterial resistance to CLPs was strongly related to energy metabolism. Using polymyxin B (PB) as a model of CLPs, we showed that PB causes malfunction of respiration and serious depletion of ATP, contributing to PB-induced cell death and carbon starvation. Glucose addition could maintain the intracellular ATP level and reverse the carbon starvation response resulting from PB treatment. Another study revealed that glycolysis was stimulated by the presence of PB and glucose. The mechanism underlying glucose-enabled CLPs' resistance suggests that glucose could maintain the ATP level in PB-treated bacteria by enhancing glycolysis. Similar results were observed in Staphylococcus aureus, where daptomycin resistance was enhanced by glucose. These findings provide insight into the mode of action of CLPs and resistance to these antibiotics.

Integrative proteomics and metabolomics approach to elucidate the antimicrobial effect of simvastatin on Escherichia coli

“…Glycolysis is the key process for energy production. Various metabolomics and proteomics analyses showed that glycolysis pathway was downregulated in antibiotic stress conditions (Stokes et al, 2019;Yu et al, 2019). In the present work, we observed that most of the altered proteins in glycolysis pathway were downregulated in simvastatin-treated samples (Figure 8a).…”

Bedaquiline reprograms central metabolism to reveal glycolytic vulnerability in Mycobacterium tuberculosis

“…Our findings are consistent with previous studies on Bacillus and Staphylococcus spp . showing that polymyxin B dysregulates OXPHOS, leading to ATP depletion, which could be reversed by substrate-level phosphorylation 62 , 63 . The authors of these studies concluded that the increased dependence on glycolysis to produce ATP induces drug resistance.…”

Mycobacterium tuberculosis H2S Functions as a Sink to Modulate Central Metabolism, Bioenergetics, and Drug Susceptibility

“…In addition, recent studies on Bacillus and Staphylococcus spp. showed that glycolysis can reverse polymyxin B-mediated ATP depletion that resulted from dysregulation of OXPHOS [ 68 , 69 ]. Secondly, H 2 S can directly target enzymes in the glycolytic pathway through persulfidation to modulate their activity [ 53 , 54 ].…”