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Drugs with new lease of life as quorum sensing inhibitors: for combating MDR Acinetobacter baumannii infections.

ABSTRACT: The emergence of multidrug-resistant (MDR) strains is a major health problem worldwide. There is an urgent need for novel strategies to combat bacterial infections caused by MDR strains like Pseudomonas aeruginosa and Acinetobacter baumannii. Quorum sensing (QS) is a critical communication system in bacterial community controlling survival and virulence. The awareness of the importance of QS in bacterial infections has stimulated research to identify QS inhibitors (QSIs) to defeat microbes. In this study, four FDA-approved drugs (besides azithromycin as positive QSI) were tested for potential QS inhibition against clinical A. baumannii isolates and P. aeruginosa (PAO1) standard strain. The inhibitory effect of these drugs on virulence factors of both microbes has been investigated. The studied virulence factors include biofilm formation, twitching and swarming motilities, proteolytic enzyme production, and resistance to oxidative stress. The four tested drugs (erythromycin, levamisole, chloroquine, and propranolol) inhibited QS in Chromobacterium violaceum by 84, 72, 55.1, and 37.3%, respectively. They also significantly inhibited virulence factors in both PAO1 and A. baumannii at sub-inhibitory concentrations. These findings were confirmed by qRT-PCR and mice mortality test, where tested drugs highly repressed the expression of abaI gene and showed significantly improved mice survival rates. In addition, molecular docking studies against AbaI and AbaR proteins of QS system in A. baumannii revealed the potential inhibition of QS by tested drugs. Beside their known activities, the tested drugs could be given new life as QSIs to combat A. baumannii nosocomial infections (alone or in combination with antimicrobials).

SUBMITTER: Seleem NM

PROVIDER: S-EPMC7180647 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Drugs with new lease of life as quorum sensing inhibitors: for combating MDR Acinetobacter baumannii infections.

Seleem Noura M NM Abd El Latif Hemat K HK Shaldam Moataz A MA El-Ganiny Amira A

European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology 20200423 9

The emergence of multidrug-resistant (MDR) strains is a major health problem worldwide. There is an urgent need for novel strategies to combat bacterial infections caused by MDR strains like Pseudomonas aeruginosa and Acinetobacter baumannii. Quorum sensing (QS) is a critical communication system in bacterial community controlling survival and virulence. The awareness of the importance of QS in bacterial infections has stimulated research to identify QS inhibitors (QSIs) to defeat microbes. In t ...[more]

PMID: 32328851

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Project description:Acinetobacter baumannii possesses a single divergent luxR/luxRI-type quorum-sensing (QS) locus named abaR/abaI This locus also contains a third gene located between abaR and abaI, which we term abaM, that codes for an uncharacterized member of the RsaM protein family known to regulate N-acylhomoserine lactone (AHL)-dependent QS in other beta- and gammaproteobacteria. Here, we show that disruption of abaM via a T26 insertion in A. baumannii strain AB5075 resulted in increased production of N-(3-hydroxydodecanoyl)-l-homoserine lactone and enhanced surface motility and biofilm formation. In contrast to the wild type and the abaI::T26 mutant, the virulence of the abaM::T26 mutant was completely attenuated in a Galleria mellonella infection model. Transcriptomic analysis of the abaM::T26 mutant revealed that AbaM differentially regulates at least 76 genes, including the csu pilus operon and the acinetin 505 lipopeptide biosynthetic operon, that are involved in surface adherence, biofilm formation and virulence. A comparison of the wild type, abaM::T26 and abaI::T26 transcriptomes, indicates that AbaM regulates ∼21% of the QS regulon including the csu operon. Moreover, the QS genes (abaI and abaR) were among the most upregulated in the abaM::T26 mutant. A. baumannii lux-based abaM reporter gene fusions revealed that abaM expression is positively regulated by QS but negatively autoregulated. Overall, the data presented in this work demonstrates that AbaM plays a central role in regulating A. baumannii QS, virulence, surface motility, and biofilm formation.IMPORTANCE Acinetobacter baumannii is a multiantibiotic-resistant pathogen of global health care importance. Understanding Acinetobacter virulence gene regulation could aid the development of novel anti-infective strategies. In A. baumannii, the abaR and abaI genes that code for the receptor and synthase components of an N-acylhomoserine (AHL) lactone-dependent quorum sensing system (QS) are separated by abaM Here, we show that although mutation of abaM increased AHL production, surface motility, and biofilm development, it resulted in the attenuation of virulence. AbaM was found to control both QS-dependent and QS-independent genes. The significance of this work lies in the identification of AbaM, an RsaM ortholog known to control virulence in plant pathogens, as a modulator of virulence in a human pathogen.

Dataset Information

Drugs with new lease of life as quorum sensing inhibitors: for combating MDR Acinetobacter baumannii infections.

Publications

Drugs with new lease of life as quorum sensing inhibitors: for combating MDR Acinetobacter baumannii infections.

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