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).

In vitro activity of biofilm inhibitors in combination with antibacterial drugs against extensively drug-resistant Acinetobacter baumannii

“…These findings are consistent with the fact that XDRAB has been increasingly isolated in clinical settings globally, which calls for combination therapy 11 . Indeed, the clinical choice of antibacterial drugs for XDRAB infections is limited, and the new therapeutic regime with combination drug use has been pursued 16,17,20,21 . Given that biofilms contribute to bacterial virulence and resistance 22 , we targeted agents with anti-biofilm property for their potential in combination drug use against A. baumannii.…”

“…Based on literature information [12][13][14][15][16][17] , we have identified a range of metal salts, biocides and conventionally used antibiotics with ability to affect bacterial biofilm formation. However, no or little data were specifically available to A. baumannii.…”

“…Control of bacterial biofilm formation is considered as one major strategy against bacterial infections, and thus efforts have been made to identify effective inhibitors that go beyond conventional antibiotics for their ability to disrupt biofilm formation 10 . For example, it has been reported that three chemical substances, zinc lactate, stannous fluoride and furanone, and two antibiotics, azithromycin and rifampicin, can inhibit bacterial biofilm formation, but cannot effectively control the infection caused by biofilm-forming bacteria [12][13][14][15][16][17] . Yet, information available is largely not specific to A. baumannii.…”

Quorum Sensing Inhibition or Quenching in Acinetobacter baumannii: The Novel Therapeutic Strategies for New Drug Development

“…Because of this, Raorane et al (2019) investigated the antibiofilm activities of 12 flavonoids and showed that curcumin and other flavonoids have the potential to control biofilm formation and virulence in A. baumannii . Similarly, according to the latest research report, four FDA-approved drugs (erythromycin, levamisole, chloroquine, and propranolol) were studied for the first time as inhibitors for QS against clinical A. baumannii ( Seleem et al, 2020 ). This study showed that antibiotics like erythromycin not only had antibacterial activity but also inhibited the formation of biofilm induced by QS.…”

PA2146 Gene Knockout Is Associated With Pseudomonas aeruginosa Pathogenicity in Macrophage and Host Immune Response

“…Exotoxin pyocyanin is one of the major virulence factors secreted by P. aeruginosa . Pyocyanin is regulated by the quorum sensing (QS) system, an important communication system that controls survival, virulence and biofilm formation in bacterial communities (Seleem et al, 2020 ). The QS system is mainly regulated by four QS network sub-systems, including the las, rhl , PQS, and IQS systems.…”