CmpX Affects Virulence in Pseudomonas aeruginosa Through the Gac/Rsm Signaling Pathway and by Modulating c-di-GMP Levels

• Published in: The Journal of membrane biology Vol. 251; no. 1; pp. 35 - 49
• Main Authors: Bhagirath, Anjali Y., Somayajula, Deepti, Li, Yanqi, Duan, Kangmin
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.02.2018; Springer Nature B.V
• Subjects: Anti-Bacterial Agents - pharmacology; antibiotic resistance and virulence; Antibiotics; Bacterial Membrane Proteins: Signal Transduction; Bacterial Proteins - metabolism; Biochemistry; Biofilms; Biofilms - drug effects; Biomedical and Life Sciences; Colonization; Detergents; Detergents - pharmacology; DNA microarrays; Gene Expression Regulation, Bacterial; GMP synthase; Guanosine; Human Physiology; Life Sciences; Membrane proteins; Pathogens; Phenotypes; Pseudomonas aeruginosa; Pseudomonas aeruginosa - drug effects; Pseudomonas aeruginosa - metabolism; Quaternary Ammonium Compounds - pharmacology; Ribonucleic acid; RNA; Sigma factor; Signal transduction; Signal Transduction - drug effects; Signaling; Tobramycin; Tobramycin - pharmacology; Transcription; Vancomycin; Vancomycin - pharmacology; Virulence; Virulence factors; Virulence Factors - metabolism; Biofilm; c-di-GMP; Phenotype microarrays; Pseudomonas aeruginosa; cmpX
• ISSN: 0022-2631; 1432-1424; 1432-1424
• DOI: 10.1007/s00232-017-9994-6

Pseudomonas aeruginosa is an ubiquitous organism which is able to infect and colonize many types of hosts including humans. Colonization of P. aeruginosa in chronic infections leads to the formation of biofilms, which are difficult to eradicate. P. aeruginosa is capable of regulating its virulence factors in response to external environment triggers and its signaling mechanism involves two-component regulatory systems and small molecules such as bis-(3′–5′)-cyclic dimeric guanosine monophosphate. PA1611-RetS-GacS/A-RsmA/Y/Z is a key regulatory pathway in P. aeruginosa that controls several virulence factors and biofilm formation. We have previously identified a conserved cytoplasmic membrane protein cmpX (PA1775), as a regulator for PA1611 expression. In this study, we demonstrate that cmpX regulates virulence, and controls biofilm formation in P. aeruginosa as well as provide evidence showing that cmpX affects Gac/Rsm pathway, possibly by modulating intra-cellular c-di-GMP levels. A cmpX knockout showed significantly decreased promoter activity of exoS (PA1362) and increased activity of small RNA, RsmY. As compared to the wild-type PAO1, cmpX mutant had elevated intracellular c-di-GMP level as measured indirectly by cdrA (PA4625) activity, as well as increased expression of wspR (PA3702), a c-di-GMP synthase. The transcription of the major outer membrane porin gene oprF (PA1777), and sigma factor sigX (PA1776) was also significantly decreased in the cmpX mutant. Biolog phenotype microarray experiments further indicated that the cmpX knockout mutant had increased sensitivity to membrane detergents and antibiotics such as lauryl sulfobetaine, tobramycin, and vancomycin. These results point to a significant role of cmpX in P. aeruginosa virulence and colonization.