The opportunistic pathogen Pseudomonas aeruginosa exploits bacterial biotin synthesis pathway to benefit its infectivity

Abstract

Pseudomonas aeruginosa is an opportunistic pathogen that predominantly causes nosocomial and community-acquired lung infections. As a member of ESKAPE pathogens, carbapenem-resistant P. aeruginosa (CRPA) compromises the limited therapeutic options, raising an urgent demand for the development of lead compounds against previously-unrecognized drug targets. Biotin is an important cofactor, of which the de novo synthesis is an attractive antimicrobial target in certain recalcitrant infections. Here we report genetic and biochemical definition of P. aeruginosa BioH (PA0502) that functions as a gatekeeper enzyme allowing the product pimeloyl-ACP to exit from fatty acid synthesis cycle and to enter the late stage of biotin synthesis pathway. In relative to Escherichia coli, P. aeruginosa physiologically requires 3-fold higher level of cytosolic biotin, which can be attributed to the occurrence of multiple biotinylated enzymes. The BioH protein enables the in vitro reconstitution of biotin synthesis. The repertoire of biotin abundance is assigned to different mouse tissues and/or organ contents, and the plasma biotin level of mouse is around 6-fold higher than that of human. Removal of bioH renders P. aeruginosa biotin auxotrophic and impairs its intra-phagosome persistence. Based on a model of CD-1 mice mimicking the human environment, lung challenge combined with systemic infection suggested that BioH is necessary for the full virulence of P. aeruginosa. As expected, the biotin synthesis inhibitor MAC13772 is capable of dampening the viability of CRPA. Notably, MAC13772 interferes the production of pyocyanin, an important virulence factor of P. aeruginosa. Our data expands our understanding of P. aeruginosa biotin synthesis relevant to bacterial infectivity. In particular, this study represents the first example of an extracellular pathogen P. aeruginosa that exploits biotin cofactor as a fitness determinant, raising the possibility of biotin synthesis as an anti-CRPA target.

Dual proteomics of infected macrophages reveal bacterial and host players involved in the Francisella intracellular life cycle and cell to cell dissemination by merocytophagy

“…Our data show that biotin biosynthesis may constitute the strongest bacterial adaptative response to the intracellular environment. This pathway is a key element for numerous pathogens such as Pseudomonas aeruginosa that is able to exploit it to benefit its infectivity 32 . In other bacteria such as Mycobacterium tuberculosis , BioA is involved in virulence in in the guinea pig model of tuberculosis 33 .…”

Rapid detection of mexX in Pseudomonas aeruginosa based on CRISPR-Cas13a coupled with recombinase polymerase amplification

“…Pseudomonas aeruginosa is an opportunistic pathogen that is commonly found in hospitals. It can cause a variety of chronic infections, including urinary tract infections, bronchial dilation, and cystic fibrosis, all of which have a high recurrence rate and are difficult to treat (Gellatly and Hancock, 2013;Diggle and Whiteley, 2020;Shi et al, 2023). In addition, P. aeruginosa can cling to various surfaces of food processing equipment to form biofilms, endangering food safety and quality and potentially causing food-borne diseases (Teng et al, 2022;Ingrid et al, 2023;Silvia et al, 2023;Wu et al, 2023).…”

Can we microbe-manage our vitamin acquisition for better health?

“…Interestingly, recent research has highlighted the importance of vitamins in the pathology of opportunistic pathogens that live as commensals in the human GI tract [ 10 , 11 ].…”

“…It has been estimated that they produce up to 30% of the recommended daily intake for the host; however, this depends on the microbiome composition and the host's diet [7]. Moreover, microbes can work together to produce vitamins that can modulate the metabolic activity and composition of the human gut microbiome [8,9].Interestingly, recent research has highlighted the importance of vitamins in the pathology of opportunistic pathogens that live as commensals in the human GI tract [10,11].…”