Colistin-degrading proteases confer collective resistance to microbial communities during polymicrobial infections

Abstract

Background The increasing prevalence of resistance against the last-resort antibiotic colistin is a significant threat to global public health. Here, we discovered a novel colistin resistance mechanism via enzymatic inactivation of the drug and proposed its clinical importance in microbial communities during polymicrobial infections. Results A bacterial strain of the Gram-negative opportunistic pathogen Stenotrophomonas maltophilia capable of degrading colistin and exhibiting a high-level colistin resistance was isolated from the soil environment. A colistin-degrading protease (Cdp) was identified in this strain, and its contribution to colistin resistance was demonstrated by growth inhibition experiments using knock-out (Δcdp) and complemented (Δcdp::cdp) mutants. Coculture and coinfection experiments revealed that S. maltophilia carrying the cdp gene could inactivate colistin and protect otherwise susceptible Pseudomonas aeruginosa, which may seriously affect the clinical efficacy of the drug for the treatment of cystic fibrosis patients with polymicrobial infection. Conclusions Our results suggest that Cdp should be recognized as a colistin resistance determinant that confers collective resistance at the microbial community level. Our study will provide vital information for successful clinical outcomes during the treatment of complex polymicrobial infections, particularly including S. maltophilia and other colistin-susceptible Gram-negative pathogens such as P. aeruginosa.

Stenotrophomonas maltophilia virulence: a current view

“… Lee et al (2022) purified and identified a serine colistin-degrading protease (Cdp) in S. maltophilia strain Col1. Isolated from the soil, this strain exhibited high-level resistance against colistin (MIC value of 32 mg/L).…”

“…In contrast, coinfection of flies with S. maltophilia strains carrying the cdp gene, did not increase the survival rate after colistin treatment. The authors noted that S. maltophilia genomes contain genes orthologous to cdp , located in a region immediately adjacent to the T2SS gene cluster ( Lee et al, 2022 ). Thus, the colistin-degrading protease may play an important role in collective resistance to colistin in polymicrobial infections such as CF ( Lee et al, 2022 ).…”

Stenotrophomonas maltophilia complex: insights into evolutionary relationships, global distribution and pathogenicity

“…Additionally, S. maltophilia can play a significant role in microbiological co-infections. For instance, S. maltophilia has been found to provide significant levels of protection against antibiotics for Pseudomonas aeruginosa , which would otherwise be susceptible to them ( Bottery et al., 2022 ; Lee et al., 2022 ) and interfere with the isolation cultures and drug sensitivity tests of Mycobacterium tuberculosis , potentially leading to alterations in treatment plans and an escalation in the burden of the disease ( Li et al., 2023 ).…”

Whole-Genome Sequencing-Based Resistome Analysis of Nosocomial Multidrug-Resistant Non-Fermenting Gram-Negative Pathogens from the Balkans

“…The last resort antibiotic colistin is also not suitable despite the demonstrated in vitro activity because half of the isolates are actually resistant to this antibiotic [ 34 ]. In addition, a recent study described a colistin-degrading protease in an environmental S. maltophilia isolate [ 35 ]. Co-cultivation experiments demonstrated that this enzyme can inactivate colistin and thereby protect an otherwise susceptible P. aeruginosa strain.…”