Drug repositioning: doxazosin attenuates the virulence factors and biofilm formation in Gram-negative bacteria

Elfaky, Mahmoud A.; Elbaramawi, Samar S.; Eissa, Ahmed G.; Ibrahim, Tarek S.; Khafagy, El-Sayed; Ali, Mohamed A.; Hegazy, Wael A. H.

doi:10.1007/s00253-023-12522-3

Cited by 19 publications

(9 citation statements)

References 90 publications

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“…The housekeeping gene rpoB was used to normalize the relative expression levels of the tested genes. The StepOne Real-Time PCR System (Applied Biosystems, United States) was utilized, and the protocol of the SensiFAST™ SYBR ® Hi-ROX One-Step Kit (Bioline, United Kingdom) was followed ( Askoura et al, 2022 ; Elfaky et al, 2023 ). The thermocycling conditions were as follows: 3 min at 95 °C for enzyme activation, followed by 40 cycles (denaturation for 15 s at 95 °C, annealing for 30 s at 50–60 C, and extension for 30 s at 72 °C).…”

Section: Methodsmentioning

confidence: 99%

Redirecting pantoprazole as a metallo-beta-lactamase inhibitor in carbapenem-resistant Klebsiella pneumoniae

Abdulaal,

Alhakamy,

Asseri

et al. 2024

Front. Pharmacol.

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The development of resistance to carbapenems in Klebsiella pneumoniae due to the production of metallo-β-lactamases (MBLs) is a critical public health problem because carbapenems are the last-resort drugs used for treating severe infections of extended-spectrum β-lactamases (ESBLs) producing K. pneumoniae. Restoring the activity of carbapenems by the inhibition of metallo-β-lactamases is a valuable approach to combat carbapenem resistance. In this study, two well-characterized clinical multidrug and carbapenem-resistant K. pneumoniae isolates were used. The sub-inhibitory concentrations of pantoprazole and the well-reported metallo-β-lactamase inhibitor captopril inhibited the hydrolytic activities of metallo-β-lactamases, with pantoprazole having more inhibiting activities. Both drugs, when used in combination with meropenem, exhibited synergistic activities. Pantoprazole could also downregulate the expression of the metallo-β-lactamase genes blaNDM and blaVIM. A docking study revealed that pantoprazole could bind to and chelate zinc ions of New Delhi and Verona integron-encoded MBL (VIM) enzymes with higher affinity than the control drug captopril and with comparable affinity to the natural ligand meropenem, indicating the significant inhibitory activity of pantoprazole against metallo-β-lactamases. In conclusion, pantoprazole can be used in combination with meropenem as a new strategy for treating serious infections caused by metallo-β-lactamases producing K. pneumoniae.

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Section: Methodsmentioning

confidence: 99%

Redirecting pantoprazole as a metallo-beta-lactamase inhibitor in carbapenem-resistant Klebsiella pneumoniae

Abdulaal,

Alhakamy,

Asseri

et al. 2024

Front. Pharmacol.

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“…The MICs of propranolol were determined against Pseudomonas aeruginosa PAO1 and Serratia marcescens clinical isolate [51], employing the agar dilution method according to the guidelines of the Clinical Laboratory and Standards Institute Guidelines (CLSI, 2015) [19,52]. To eliminate any potential influence on bacterial growth, bacterial viable counts were performed for overnight cultures of the tested strains at sub-MIC (1/4 MIC) in Luria Bertani Broth (LB) [18,38].…”

Section: Minimum Inhibitory Concentrations (Mics)mentioning

confidence: 99%

“…The extracellular produced proteases were assessed in the supernatants of the overnight cultures using the skim milk agar method [19,57]. The tested bacteria were overnight cultured at 37 • C in the presence or absence of propranolol at sub-MIC, and the supernatants containing the produced extracellular enzymes were collected by centrifugation.…”

Section: Protease Assaymentioning

confidence: 99%

“…This approach has been suggested to overcome bacterial resistance development, as mitigating the virulence without affecting the growth could enhance the immunity to remove bacteria without stressing them to develop resistance [15][16][17]. There are several studies that investigate the potential of employing FDA-approved safe drugs as antibacterial agents [18][19][20][21][22][23], natural products [24][25][26][27][28], and several chemical moieties [29][30][31]. Drug repurposing refers to the process of identifying new uses for existing drugs that were originally developed for a different therapeutic indication [32].…”

Section: Introductionmentioning

confidence: 99%

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The Anti-Virulence Activities of the Antihypertensive Drug Propranolol in Light of Its Anti-Quorum Sensing Effects against Pseudomonas aeruginosa and Serratia marcescens

Alotaibi,

Darwish

et al. 2023

Biomedicines

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The development of bacterial resistance is an increasing global concern that requires discovering new antibacterial agents and strategies. Bacterial quorum sensing (QS) systems play important roles in controlling bacterial virulence, and their targeting could lead to diminishing bacterial pathogenesis. In this context, targeting QS systems without significant influence on bacterial growth is assumed as a promising strategy to overcome resistance development. This study aimed at evaluating the anti-QS and anti-virulence activities of the β-adrenoreceptor antagonist propranolol at sub-minimal inhibitory concentrations (sub-MIC) against two Gram-negative bacterial models Pseudomonas aeruginosa and Serratia marcescens. The effect of propranolol on the expression of QS-encoding genes was evaluated. Additionally, the affinity of propranolol to QS receptors was virtually attested. The influence of propranolol at sub-MIC on biofilm formation, motility, and production of virulent factors was conducted. The outcomes of the propranolol combination with different antibiotics were assessed. Finally, the in vivo protection assay in mice was performed to assess propranolol’s effect on lessening the bacterial pathogenesis. The current findings emphasized the significant ability of propranolol at sub-MIC to reduce the formation of biofilms, motility, and production of virulence factors. In addition, propranolol at sub-MIC decreased the capacity of tested bacteria to induce pathogenesis in mice. Furthermore, propranolol significantly downregulated the QS-encoding genes and showed significant affinity to QS receptors. Finally, propranolol at sub-MIC synergistically decreased the MICs of different antibiotics against tested bacteria. In conclusion, propranolol might serve as a plausible adjuvant therapy with antibiotics for the treatment of serious bacterial infections after further pharmacological and pharmaceutical studies.

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“…The formation of biofilms has significant implications for both the virulence of bacteria and their resistance to antibiotics. In terms of virulence, the biofilm matrix constitutes a protective barrier that hinders the access of immune cells to the bacteria within the biofilm and help the biofilm cells to resist the host immunity ( Elfaky et al., 2023 ; Rajab and Hegazy, 2023 ). The complex architecture of biofilms allows bacteria to establish persistent infections ( Hegazy and Abbas, 2017 ; Cavalu et al., 2022 ).…”

Section: Introductionmentioning

confidence: 99%

Thymoquinone is a natural antibiofilm and pathogenicity attenuating agent in Pseudomonas aeruginosa

Al-Rabia,

Asfour,

Alhakamy

et al. 2024

Front. Cell. Infect. Microbiol.

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Pseudomonas aeruginosa belongs to the critical pathogens that represent a global public health problem due to their high rate of resistance as listed by WHO. P. aeruginosa can result in many nosocomial infections especially in individuals with compromised immune systems. Attenuating virulence factors by interference with quorum sensing (QS) systems is a promising approach to treat P. aeruginosa-resistant infections. Thymoquinone is a natural compound isolated from Nigella sativa (black seed) essential oil. In this study, the minimum inhibitory concentration of thymoquinone was detected followed by investigating the antibiofilm and antivirulence activities of the subinhibitory concentration of thymoquinone against P. aeruginosa PAO1. The effect of thymoquinone on the expression of QS genes was assessed by quantitative real-time PCR, and the protective effect of thymoquinone against the pathogenesis of PAO1 in mice was detected by the mouse survival test. Thymoquinone significantly inhibited biofilm, pyocyanin, protease activity, and swarming motility. At the molecular level, thymoquinone markedly downregulated QS genes lasI, lasR, rhlI, and rhlR. Moreover, thymoquinone could protect mice from the pathologic effects of P. aeruginosa increasing mouse survival from 20% to 100%. In conclusion, thymoquinone is a promising natural agent that can be used as an adjunct therapeutic agent with antibiotics to attenuate the pathogenicity of P. aeruginosa.

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Drug repositioning: doxazosin attenuates the virulence factors and biofilm formation in Gram-negative bacteria

Cited by 19 publications

References 90 publications

Redirecting pantoprazole as a metallo-beta-lactamase inhibitor in carbapenem-resistant Klebsiella pneumoniae

Redirecting pantoprazole as a metallo-beta-lactamase inhibitor in carbapenem-resistant Klebsiella pneumoniae

The Anti-Virulence Activities of the Antihypertensive Drug Propranolol in Light of Its Anti-Quorum Sensing Effects against Pseudomonas aeruginosa and Serratia marcescens

Thymoquinone is a natural antibiofilm and pathogenicity attenuating agent in Pseudomonas aeruginosa

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