Abstract
Antimicrobial resistance is one of the current public health challenges to be solved. The World Health Organization (WHO) has urgently called for the development of strategies to expand the increasingly limited antimicrobial arsenal. The development of anti-virulence therapies is a viable option to counteract bacterial infections with the possibility of reducing the generation of resistance. Here we report on the chemical structures of pyrrolidones DEXT 1–4 (previously identified as furan derivatives) and their anti-virulence activity on Pseudomonas aeruginosa strains. DEXT 1–4 were shown to inhibit biofilm formation, swarming motility, and secretion of ExoU and ExoT effector proteins. Also, the anti-pathogenic property of DEXT-3 alone or in combination with furanone C-30 (quorum sensing inhibitor) or MBX-1641 (type III secretion system inhibitor) was analyzed in a model of necrosis induced by P. aeruginosa PA14. All treatments reduced necrosis; however, only the combination of C-30 50 µM with DEXT-3 100 µM showed significant inhibition of bacterial growth in the inoculation area and systemic dispersion. In conclusion, pyrrolidones DEXT 1–4 are chemical structures capable of reducing the pathogenicity of P. aeruginosa and with the potential for the development of anti-virulence combination therapies.
Highlights
Multiple reports in the specialized literature indicate that bacterial multidrug resistance (MDR) is an emerging global public health problem
The pathogenicity of P. aeruginosa can be explained by the production of several virulence factors such as exoproteases, toxins, pyocyanin, rhamnolipids, and swarming motility regulated by quorum sensing systems (QSS) [3]
These results demonstrate that the previously published compounds as halogen-4-alkyl-5-phenyl3-(phenylamino)-furan-2-(5H)-one-type derivatives [19] correspond to the pyrrolidone derivatives DEXT 1–4 and highlights the difficulty to discriminate between the pyrrolidone structures 1-4 and the previously reported furanones using conventional spectroscopy
Summary
Multiple reports in the specialized literature indicate that bacterial multidrug resistance (MDR) is an emerging global public health problem. The World Health Organization (WHO) announced a list of priority microbes that need to be fought due to their high resistance rates, and Pseudomonas aeruginosa is one of the main ones considered critical [1]. This bacterium is the most common Gram-negative pathogen that causes nosocomial pneumonia. QSS inhibition is presented as an alternative to eliminate infections caused by MDR bacteria [5]. Because this therapy does not exert direct selection pressure, it may have a low probability of developing resistance [6,7]
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