Bacterial defenses against a natural antibiotic promote collateral resilience to clinical antibiotics

• Published in: PLoS biology 2021-03, Vol.19 (3), p.e3001093
• Main Authors: Meirelles, Lucas A, Perry, Elena K, Bergkessel, Megan, Newman, Dianne K
• Format: Article
• Language: English
• Subjects: Analysis; Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - therapeutic use; Antibiotic resistance; Antibiotic tolerance; Antibiotics; Bacteria - drug effects; Bacteria - genetics; Bacteria - metabolism; Biology and Life Sciences; Burkholderia cepacia - drug effects; Burkholderia cepacia - genetics; Burkholderia cepacia - metabolism; Carbon; Cell walls; Datasets; Drug resistance; Drug resistance in microorganisms; Drug Resistance, Bacterial - drug effects; Drug Resistance, Bacterial - genetics; Efflux; Evolution; Fitness; Genes; Genetic aspects; Genomes; Heterocyclic compounds; Humans; Identification and classification; Infections; Medicine and Health Sciences; Membrane permeability; Membrane proteins; Membranes; Metabolism; Microbial Sensitivity Tests; Opportunistic Infections - drug therapy; Opportunistic Infections - microbiology; Oxidative stress; Pathogens; Phenazine; Physical Sciences; Properties; Proteins; Pseudomonas aeruginosa; Pseudomonas aeruginosa - drug effects; Pseudomonas aeruginosa - genetics; Pseudomonas aeruginosa - metabolism; Public health; Pyocyanine - metabolism; Repressors; Reproductive fitness; Toxicity; Variance analysis
• ISSN: 1545-7885; 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.3001093

Bacterial opportunistic human pathogens frequently exhibit intrinsic antibiotic tolerance and resistance, resulting in infections that can be nearly impossible to eradicate. We asked whether this recalcitrance could be driven by these organisms' evolutionary history as environmental microbes that engage in chemical warfare. Using Pseudomonas aeruginosa as a model, we demonstrate that the self-produced antibiotic pyocyanin (PYO) activates defenses that confer collateral tolerance specifically to structurally similar synthetic clinical antibiotics. Non-PYO-producing opportunistic pathogens, such as members of the Burkholderia cepacia complex, likewise display elevated antibiotic tolerance when cocultured with PYO-producing strains. Furthermore, by widening the population bottleneck that occurs during antibiotic selection and promoting the establishment of a more diverse range of mutant lineages, PYO increases apparent rates of mutation to antibiotic resistance to a degree that can rival clinically relevant hypermutator strains. Together, these results reveal an overlooked mechanism by which opportunistic pathogens that produce natural toxins can dramatically modulate the efficacy of clinical antibiotics and the evolution of antibiotic resistance, both for themselves and other members of clinically relevant polymicrobial communities.