Selective inhibition of anaerobic ubiquinone biosynthesis in Pseudomonas aeruginosa
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Pseudomonas aeruginosa is a metabolically versatile opportunistic pathogen capable of adapting to diverse and challenging environments, including the oxygen- and nutrient-limited conditions encountered during chronic infections. Its ability to utilize a broad range of carbon sources and to switch from aerobic to anaerobic respiration contributes to its persistence within the host and its resilience to therapeutic interventions. In particular, denitrification enables P. aeruginosa to grow under oxygen-limited conditions by using nitrate and nitrite as alternative electron acceptors, a process particularly relevant in biofilms and chronic infections such as cystic fibrosis. Ubiquinone (UQ) is essential for respiratory metabolism in P. aeruginosa , which possesses two distinct UQ biosynthetic pathways that ensure UQ production across a broad range of oxygen concentrations. Recent studies have identified the O 2 -independent UQ biosynthetic pathway as a key determinant of chronic infection. Because this pathway is restricted to a limited group of bacteria, we hypothesized that its selective inhibition could represent a strategy to specifically target P. aeruginosa under anaerobic conditions. To test this hypothesis, we screened analogues of 4-hydroxybenzoic acid (4-HB), the earliest precursor of the UQ biosynthetic pathway, and identified 4-aminobenzoic acid, also known as para-aminobenzoic acid (pABA), as a potential inhibitor. pABA primarily affects the anaerobic metabolism of P. aeruginosa by acting as a competing substrate for UQ biosynthetic enzymes, thereby interfering with UQ biosynthesis. This inhibitory effect positions pABA as a valuable tool for investigating, and potentially targeting, anaerobic metabolism in P. aeruginosa .
Importance
Pseudomonas aeruginosa is a metabolically versatile bacterium that thrives in diverse environments, including clinical settings, where it poses a major threat due to its antibiotic resistance and adaptability. Its ability to survive under both oxygen-rich and oxygen-limited conditions, through processes such as denitrification, facilitates persistence during chronic infections such as cystic fibrosis. Central to its respiratory metabolism is ubiquinone (UQ), which is essential under all oxygen conditions. P. aeruginosa possesses two UQ biosynthetic pathways: an O 2 -dependent and an O 2 -independent one, the latter being crucial for anaerobic survival. This pathway, widespread among Pseudomonadota , is associated with the maintenance of chronic infection. Thus, targeting this O 2 -independent UQ pathway represents a promising strategy for novel antimicrobial development. In this context, we have identified para-aminobenzoic acid as a potential inhibitor.
