Abstract
Bacteria can be refractory to antibiotics due to a sub-population of dormant cells, called persisters that are highly tolerant to antibiotic exposure. The low frequency and transience of the antibiotic tolerant “persister” trait has complicated elucidation of the mechanism that controls antibiotic tolerance. In this study, we show that 2’ Amino-acetophenone (2-AA), a poorly studied but diagnostically important small, volatile molecule produced by the recalcitrant gram-negative human pathogen Pseudomonas aeruginosa, promotes antibiotic tolerance in response to quorum-sensing (QS) signaling. Our results show that 2-AA mediated persister cell accumulation occurs via alteration of the expression of genes involved in the translational capacity of the cell, including almost all ribosomal protein genes and other translation-related factors. That 2-AA promotes persisters formation also in other emerging multi-drug resistant pathogens, including the non 2-AA producer Acinetobacter baumannii implies that 2-AA may play an important role in the ability of gram-negative bacteria to tolerate antibiotic treatments in polymicrobial infections. Given that the synthesis, excretion and uptake of QS small molecules is a common hallmark of prokaryotes, together with the fact that the translational machinery is highly conserved, we posit that modulation of the translational capacity of the cell via QS molecules, may be a general, widely distributed mechanism that promotes antibiotic tolerance among prokaryotes.
Highlights
Antibiotic tolerance, observed in a broad range of microbial species, is the capacity of bacterial sub-populations to tolerate exposure to normally lethal concentrations of bactericidal antibiotics [1,2]
These results demonstrate that the small volatile quorum sensing (QS) molecule 2’ Aminoacetophenone (2-anthranilic acid (AA)) promotes persisters formation in P. aeruginosa
It is well documented that QS is mediated by diffusible small molecules that serve as intricate signals to exert transcriptional control over a vast array of genes, many of which encode virulence factors [42]
Summary
Antibiotic tolerance, observed in a broad range of microbial species, is the capacity of bacterial sub-populations to tolerate exposure to normally lethal concentrations of bactericidal antibiotics [1,2]. 2-AA, along with a large number of small molecules including 4-hydroxy-2-alkylquinolines (HAQs), is synthesized by pqsABCD operon enzymes [12,18,28,29], which are under the transcriptional control of MvfR [12,18,28,29] This non-HAQ molecule, is an abundant MvfR-regulated molecule that mediates phenotypic changes in a sub-population of cells which may contribute to chronic infections by stochastically silencing acute virulence functions in P. aeruginosa [29]. These findings, combined with the presence of 2-AA in difficult to treat P. aeruginosa-infected burn wounds [27] and P. aeruginosa clinical isolates from cystic fibrosis patients [31], prompted us to hypothesize that 2-AA may be involved in P. aeruginosa antibiotic tolerance
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