Nutrient Limitation Sensitizes Pseudomonas aeruginosa to Vancomycin

• DOI: 10.1021/acsinfecdis.3c00167
• Publication Date: 2023-06-07T02:51:57Z
• Authors: Derek C. K. Chan; Katherine Dykema; Mahrukh Fatima; Hanjeong Harvey; Ikram Qaderi; Lori L. Burrows
• Keywords: Vancomycin; Pseudomonas aeruginosa; Glycopeptides; Nutrients; Anti-Bacterial Agents

Traditional antibacterial screens rely on growing bacteria in nutrient-replete conditions which are not representative of the natural environment or sites infection. Instead, screening more physiologically relevant may reveal novel activity for existing antibiotics. Here, we screened a panel antibiotics reported to lack against opportunistic Gram-negative bacterium, Pseudomonas aeruginosa, under low-nutrient and low-iron conditions, discovered that glycopeptide vancomycin inhibited growth P. aeruginosa at low micromolar concentrations through its canonical mechanism action, disruption peptidoglycan crosslinking. Spontaneous vancomycin-resistant mutants underwent activating mutations sensor kinase two-component CpxSR system, induced cross-resistance almost all classes β-lactams, including siderophore antibiotic cefiderocol. Other conferred resistance mapped WapR, an α-1,3-rhamnosyltransferase involved lipopolysaccharide core biosynthesis. A WapR P164T mutant had modified LPS profile compared wild type was accompanied by increased susceptibility select bacteriophages. We conclude nutrient-limited can lead discovery new impactful mechanisms.