In vitro synergistic effect of amlodipine and imipenem on the expression of the AdeABC efflux pump in multidrug-resistant Acinetobacter baumannii

Hu, Chao; Li, Yujun; Zhao, Zhihui; Wei, Shuquan; Zhao, Zhenzhen; Hui-ling, Chen; Wu, Pei-Lian

doi:10.1371/journal.pone.0198061

Cited by 15 publications

(12 citation statements)

References 30 publications

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“…Resistance phenotypes but not resistance mechanisms were described for these test strains so that it may be probable but it is not proven that antibiotic resistances were caused by efflux mechanisms which were inhibited by calcium channel blockers. Likewise, amlodipine enhanced the activities of imipenem against multidrug-resistant A. baumanii by inhibiting expression of the resistance nodulation cell division efflux pump AdeABC [173]. Verapamil is assumed to be an inhibitor of P-glycoprotein and efflux pumps in M. tuberculosis and other bacterial species, so that its potentiating activity was attributed to an intraphagocytic and/or intrabacterial drug accumulation [157,[169][170][171][172][173][174][175][176][177] and also increased bioavailability due to interaction with CYP3A4 [157,178].…”

Section: Calcium Channel Blockersmentioning

confidence: 99%

Section: Calcium Channel Blockersmentioning

confidence: 99%

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Are antibacterial effects of non-antibiotic drugs random or purposeful because of a common evolutionary origin of bacterial and mammalian targets?

Dalhoff

2020

Infection

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Purpose Advances in structural biology, genetics, bioinformatics, etc. resulted in the availability of an enormous pool of information enabling the analysis of the ancestry of pro- and eukaryotic genes and proteins. Methods This review summarizes findings of structural and/or functional homologies of pro- and eukaryotic enzymes catalysing analogous biological reactions because of their highly conserved active centres so that non-antibiotics interacted with bacterial targets. Results Protease inhibitors such as staurosporine or camostat inhibited bacterial serine/threonine or serine/tyrosine protein kinases, serine/threonine phosphatases, and serine/threonine kinases, to which penicillin-binding-proteins are linked, so that these drugs synergized with β-lactams, reverted aminoglycoside-resistance and attenuated bacterial virulence. Calcium antagonists such as nitrendipine or verapamil blocked not only prokaryotic ion channels but interacted with negatively charged bacterial cell membranes thus disrupting membrane energetics and inducing membrane stress response resulting in inhibition of P-glycoprotein such as bacterial pumps thus improving anti-mycobacterial activities of rifampicin, tetracycline, fluoroquinolones, bedaquilin and imipenem-activity against Acinetobacter spp. Ciclosporine and tacrolimus attenuated bacterial virulence. ACE-inhibitors like captopril interacted with metallo-β-lactamases thus reverting carbapenem-resistance; prokaryotic carbonic anhydrases were inhibited as well resulting in growth impairment. In general, non-antibiotics exerted weak antibacterial activities on their own but synergized with antibiotics, and/or reverted resistance and/or attenuated virulence. Conclusions Data summarized in this review support the theory that prokaryotic proteins represent targets for non-antibiotics because of a common evolutionary origin of bacterial- and mammalian targets resulting in highly conserved active centres of both, pro- and eukaryotic proteins with which the non-antibiotics interact and exert antibacterial actions.

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Section: Calcium Channel Blockersmentioning

confidence: 99%

Section: Calcium Channel Blockersmentioning

confidence: 99%

Are antibacterial effects of non-antibiotic drugs random or purposeful because of a common evolutionary origin of bacterial and mammalian targets?

Dalhoff

2020

Infection

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“…Amlodipine is among the best-studied agents that reverse resistance of Plasmodium to antimalarial agents (28), and accumulating evidence suggests that some CCBs can enhance the antifungal activity of azole derivatives by interfering with efflux pumps and/or influencing calcium signaling pathways (26,27). The drug has also exhibited broad-spectrum antibacterial activities and in vitro synergistic antimicrobial effects on multidrug-resistant microorganisms (29). Notably, positive interactions between CCBs and nitroheterocyclic or azolic compounds have been documented against T. cruzi infections in experimental models (13,14).…”

Section: Discussionmentioning

confidence: 99%

“…Ravuconazole is a moderate inhibitor of CYP3A4 (31), and inhibition of this enzyme could lead to increased exposure levels of the partner drug and thus contribute to increasing its trypanocidal activity in host tissues in vivo. Alternatively, one may hypothesize that amlodipine could interfere with efflux pump activity (29,32), thereby increasing the bioavailability of ravuconazole. Thus, combination therapy using ravuconazole and amlodipine can be considered promising and deserves further detailed investigation related to the pharmacokinetic/pharmacodynamic (PK/PD) properties of the drug combination.…”

Section: Discussionmentioning

confidence: 99%

Amlodipine Increases the Therapeutic Potential of Ravuconazole upon Trypanosoma cruzi Infection

Machado

Bahia

Caldas

et al. 2020

Antimicrob Agents Chemother

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Mining existing agents that enhance the therapeutic potential of ergosterol biosynthesis inhibitors (EBI) is a promising approach to improve Chagas disease chemotherapy. In this study, we evaluated the effect of ravuconazole, an EBI, combined with amlodipine, a calcium channel blocker, upon Trypanosoma cruzi experimental infection. In vitro assays confirmed the trypanocidal activity of both compounds in monotherapy and demonstrated an additive effect (sum of the fractional inhibitory concentration [ΣFIC] > 0.5) of the combined treatment without additional toxicity to host cells. In vivo experiments, using a murine model of the T. cruzi Y strain in a short-term protocol, demonstrated that amlodipine, although lacking trypanocidal activity, dramatically increased the antiparasitic activity of underdosing ravuconazole regimens. Additional analysis using long-term treatment (20 days) showed that parasitemia relapse until 60 days after treatment was significatively lower in mice treated with the combination (4 out of 14 mice) than ravuconazole monotherapy (10 out of 14 mice), even in the presence of immunosuppressant pressure. Furthermore, the combined therapy was well tolerated and protected the mice from mortality. The treatments also impacted on the cellular and humoral immune response of infected animals, inducing a reduction of serum cytokine levels in all ravuconazole-treated mice. Our findings demonstrate that amlodipine is efficacious in enhancing the antiparasitic activity of ravuconazole in an experimental model of T. cruzi infection and indicates a potential strategy to be explored in Chagas disease treatment.

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“…[2][3][4] In a recent study and clinical trial, amlodipine was discovered to also reverse the antibiotic resistance of A. baumannii. [5][6] However, no study of the relationship between amlodipine and gram positive resistant bacteria has been conducted.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Amlodipine Inhibition and Antimicrobial Effects

Yi¹,

Zhu²,

Ma³

2019

IJPC

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Antibiotic resistant pathogens is the an urgent challenge of the medicine field. To counter these pathogens, the antibiotic assisting drugs is an ideal choice. Assisting drugs can improve the efficiency of the treatment without further induce of antibiotic resistance. Amlodipine (AML) is one of the most common generic cardiovascular drug for lowering blood pressure. In previous studies, amlodipine was suggested to have some antibiotic properties. The MIC is not very low for amlodipine against these pathogens. However, the findings imply amlodipine potential to be repurposed as assisting drug and its inhibition of β-lactamase. To further discover and verify its potential of antimicrobial drug, amlodipine was tested for β-lactamase inhibition, and its synergistic effects were investigated against methicillin-resistant Staphylococcus aureus (MRSA). The compound was found to inhibit β-lactamase mixture (3 distinct species) in broad spectrum. Cephalosporins requires high concentration (>=64 ug/ml) to inhibit MRSA; combine both amlodipine and cephalosporins, the MIC only requires 8ug/ml (4 ug/ml amlodipine + 4 ug/ml Cefuroxime) in total, with FIC lower than 0.1 for strong synergistic effect. Both enzyme assay and bacterial tests indicate amlodipine as an ideal assisting drug for antibiotics; one of the mechanism is β-lactamase inhibition.

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In vitro synergistic effect of amlodipine and imipenem on the expression of the AdeABC efflux pump in multidrug-resistant Acinetobacter baumannii

Cited by 15 publications

References 30 publications

Are antibacterial effects of non-antibiotic drugs random or purposeful because of a common evolutionary origin of bacterial and mammalian targets?

Are antibacterial effects of non-antibiotic drugs random or purposeful because of a common evolutionary origin of bacterial and mammalian targets?

Amlodipine Increases the Therapeutic Potential of Ravuconazole upon Trypanosoma cruzi Infection

Evaluation of Amlodipine Inhibition and Antimicrobial Effects

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