Pseudomonas aeruginosa defense systems against microbicidal oxidants

4 years ago

Pseudomonas aeruginosa defense systems against microbicidal oxidants

Bastian Groitl, Jan-Ulrik Dahl, Ursula Jakob, Jeremy W. Schroeder

The most abundant oxidants controlling bacterial colonization on mucosal barrier epithelia are hypochlorous acid (HOCl), hypobromous acid (HOBr) and hypothiocyanous acid (HOSCN). All three oxidants are highly antimicrobial but little is known about their relative efficacies, their respective cellular targets, or what specific responses they elicit in bacteria. To address these important questions, we directly tested the individual oxidants on the virulent Pseudomonas aeruginosa strain PA14. We discovered that HOCl and HOBr work almost interchangeably, impacting non-growing bacterial cultures more significantly than actively growing bacteria, and eliciting similar stress responses, including the heat shock response. HOSCN treatment is distinctly different, affecting primarily actively growing PA14 and evoking stress responses suggestive of membrane damage. What all three oxidants have in common, however, is their ability to cause substantial protein aggregation. This effect became particularly obvious in strains lacking polyphosphate, a newly recognized chemical chaperone. Treatment of PA14 with the FDA-approved anti-inflammatory drug mesalamine, which has recently been shown to attenuate polyP production in a wide range of bacteria, effectively decreased the resistance of PA14 toward all three oxidants, suggesting that we have discovered a novel, targetable defense system in P. aeruginosa. Accumulation of polyphosphate serves as the universal strategy of P. aeruginosa to respond to and resist the host-induced production of antimicrobial oxidants by reducing oxidative protein unfolding and aggregation. Impairment of polyphosphate production caused by the FDA-approved drug mesalamine sensitizes the pathogen toward all three physiological oxidants making mesalamine potentially an attractive new treatment option to improve the ability of the endogenous host defense systems to kill stress-resistant microbes.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/mmi.13768