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

Abstract

As antibiotic-resistant infections become increasingly prevalent worldwide, understanding the factors that lead to antimicrobial treatment failure is essential to optimizing the use of existing drugs. Opportunistic human pathogens in particular typically exhibit high levels of intrinsic antibiotic resistance and tolerance 1 , leading to chronic infections that can be nearly impossible to eradicate 2 . We asked whether the recalcitrance of these organisms to antibiotic treatment could be driven in part by their evolutionary history as environmental microbes, which frequently produce or encounter natural antibiotics 3,4 . Using the opportunistic pathogen Pseudomonas aeruginosa as a model, we demonstrate that the self-produced natural antibiotic pyocyanin (PYO) activates bacterial defenses that confer collateral tolerance to certain synthetic antibiotics, including in a clinically-relevant growth medium. Non-PYO-producing opportunistic pathogens isolated from lung infections similarly display increased antibiotic tolerance when they are co-cultured with PYO-producing P. aeruginosa. Furthermore, we show that beyond promoting bacterial survival in the presence of antibiotics, PYO can increase the apparent rate of mutation to antibiotic resistance by up to two orders of magnitude. Our work thus suggests that bacterial production of natural antibiotics in infections could play an important role in modulating not only the immediate efficacy of clinical antibiotics, but also the rate at which antibiotic resistance arises in multispecies bacterial communities.

Computationally designed pyocyanin demethylase acts synergistically with tobramycin to kill recalcitrant Pseudomonas aeruginosa biofilms

“…The availability of a functionally expressible design enabled physiological studies that would have been practically inaccessible otherwise. Because PYO and other phenazines permit P. aeruginosa to adopt metabolic strategies that lead to evasion of antibiotic treatments (10)(11)(12), it stands to reason that removal of these metabolites might offer an attractive therapeutic approach. Our results showing enhancement of synergistic killing by a designed PodA and tobramycin provide further motivation and the means to explore PodA's potential to be used as a biologic therapeutic for treating chronic P. aeruginosa infections.…”

“…PYO confers a competitive advantage for P. aeruginosa by contributing to iron acquisition (6), anaerobic energy conservation (7), signaling (8), and biofilm development (9). It has also been shown that P. aeruginosa cells lacking the ability to synthesize phenazines (10), and PYO in particular (11), are more sensitive to conventional antibiotics when grown both planktonically and in the biofilm state; the mechanisms underpinning these phenomena are beginning to be elucidated (12). Accordingly, we reasoned that enzymatically degrading PYO within P. aeruginosa biofilms might improve conventional drug treatment, representing a strategy for biofilm control.…”