Zafirlukast induces DNA condensation and has bactericidal effect on replicating Mycobacterium abscessus .

Autor:	Niet Svd; Electron Microscopy Centre Amsterdam, Amsterdam University Medical Centre, Amsterdam, the Netherlands., Green KD; College of Pharmacy, University of Kentucky, Lexington, Kentucky, USA., Schimmel IM; Electron Microscopy Centre Amsterdam, Amsterdam University Medical Centre, Amsterdam, the Netherlands., Bakker Jd; Electron Microscopy Centre Amsterdam, Amsterdam University Medical Centre, Amsterdam, the Netherlands., Lodder B; Electron Microscopy Centre Amsterdam, Amsterdam University Medical Centre, Amsterdam, the Netherlands., Reits EA; Electron Microscopy Centre Amsterdam, Amsterdam University Medical Centre, Amsterdam, the Netherlands., Garneau-Tsodikova S; College of Pharmacy, University of Kentucky, Lexington, Kentucky, USA., van der Wel NN; Electron Microscopy Centre Amsterdam, Amsterdam University Medical Centre, Amsterdam, the Netherlands.
Jazyk:	angličtina
Zdroj:	Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2024 Aug 07; Vol. 68 (8), pp. e0002924. Date of Electronic Publication: 2024 Jul 11.
DOI:	10.1128/aac.00029-24
Abstrakt:	Mycobacterium abscessus infections are emerging in cystic fibrosis patients, and treatment success rate in these patients is only 33% due to extreme antibiotic resistance. Thus, new treatment options are essential. An interesting target could be Lsr2, a nucleoid-associated protein involved in mycobacterial virulence. Zafirlukast is a Food and Drug Administration (FDA)-approved drug against asthma that was shown to bind Lsr2. In this study, zafirlukast treatment is shown to reduce M. abscessus growth, with a minimal inhibitory concentration of 16 µM and a bactericidal concentration of 64 µM in replicating bacteria only. As an initial response, DNA condensation, a known stress response of mycobacteria, occurs after 1 h of treatment with zafirlukast. During continued zafirlukast treatment, the morphology of the bacteria alters and the structural integrity of the bacteria is lost. After 4 days of treatment, reduced viability is measured in different culture media, and growth of M. abscessus is reduced in a dose-dependent manner. Using transmission electron microscopy, we demonstrated that the hydrophobic multilayered cell wall and periplasm are disorganized and ribosomes are reduced in size and relocalized. In summary, our data demonstrate that zafirlukast alters the morphology of M. abscessus and is bactericidal at 64 µM. The bactericidal concentration of zafirlukast is relatively high, and it is only effective on replicating bacteria but as zafirlukast is an FDA-approved drug, and currently used as an anti-asthma treatment, it could be an interesting drug to further study in in vivo experiments to determine whether it could be used as an antibiotic for M. abscessus infections. Competing Interests: The authors declare no conflict of interest.
Databáze:	MEDLINE
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