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

Area of Science:

• Microbiology
• Antimicrobial Resistance
• Enzymology

Background:

• Colistin is a last-resort antibiotic facing increasing resistance, posing a global public health threat.
• Understanding novel resistance mechanisms is critical for developing effective treatment strategies.

Purpose of the Study:

• To discover and characterize a new mechanism of colistin resistance.
• To investigate the role of this mechanism in polymicrobial infections and its clinical implications.

Main Methods:

• Isolation and identification of a colistin-degrading bacterial strain (Stenotrophomonas maltophilia).
• Identification and characterization of the colistin-degrading protease (Cdp).
• Genetic manipulation (knock-out and complemented mutants) and phenotypic analysis (growth inhibition, coculture, coinfection experiments).

Main Results:

• A novel colistin resistance mechanism was identified, mediated by enzymatic inactivation of colistin via a protease (Cdp) from S. maltophilia.
• S. maltophilia expressing Cdp demonstrated high-level colistin resistance and could protect susceptible Pseudomonas aeruginosa in coculture and coinfection models.
• This inactivation of colistin by Cdp has significant implications for treating polymicrobial infections, potentially compromising antibiotic efficacy.

Conclusions:

• Cdp is a colistin resistance determinant conferring collective resistance at the microbial community level.
• This discovery provides vital information for managing complex polymicrobial infections involving S. maltophilia and susceptible Gram-negative pathogens like P. aeruginosa.
• Recognizing Cdp's role is essential for improving clinical outcomes in challenging infections.