Efflux pump inhibitors for bacterial pathogens

Sharma, Atin; Gupta, Vivek Kumar; Pathania, Ranjana

doi:10.4103/ijmr.ijmr_2079_17

Cited by 268 publications

(163 citation statements)

References 101 publications

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“…From a therapeutic perspective, utilizing a chemical combination in which one compound targets an essential process and the other disables a major resistance mechanism provides an attractive strategy that has been explored for both antimicrobial and cancer treatment 39 , 52 , 63 – 66 . In the case of efflux inhibitors, not only does this strategy enhance the efficacy of the other compound, but if applied early in the course of intervention, it can also reduce the rate at which resistance emerges 39 , 67 .…”

Section: Discussionmentioning

confidence: 99%

An oxindole efflux inhibitor potentiates azoles and impairs virulence in the fungal pathogen Candida auris

et al. 2020

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Candida auris is an emerging fungal pathogen that exhibits resistance to multiple drugs, including the most commonly prescribed antifungal, fluconazole. Here, we use a combinatorial screening approach to identify a bis-benzodioxolylindolinone (azoffluxin) that synergizes with fluconazole against C. auris. Azoffluxin enhances fluconazole activity through the inhibition of efflux pump Cdr1, thus increasing intracellular fluconazole levels. This activity is conserved across most C. auris clades, with the exception of clade III. Azoffluxin also inhibits efflux in highly azole-resistant strains of Candida albicans, another human fungal pathogen, increasing their susceptibility to fluconazole. Furthermore, azoffluxin enhances fluconazole activity in mice infected with C. auris, reducing fungal burden. Our findings suggest that pharmacologically targeting Cdr1 in combination with azoles may be an effective strategy to control infection caused by azole-resistant isolates of C. auris.

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Section: Discussionmentioning

confidence: 99%

An oxindole efflux inhibitor potentiates azoles and impairs virulence in the fungal pathogen Candida auris

et al. 2020

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“…In addition, Se-K1 was also interesting, as it showed a biofilm inhibiting effect higher than 50% against MRSA. It was surprising that Se-K2 promoted the biofilm formation of S. aureus MRSA, because it has the same chemical formula as Se-K1 (both are 2-oxopropyl selenodiesters); they only differ in the substitution pattern at the phenyl ring, such that Se-K1 has a para substitution (1,4) and Se-K2 has a meta substitution (1,3). It is interesting to see how such a small change in the substitution pattern at the core phenyl ring leads to completely different activities.…”

Section: Discussionmentioning

confidence: 99%

Biofilm Eradication by Symmetrical Selenoesters for Food-Borne Pathogens

et al. 2020

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Infections caused by Salmonella species and Staphylococcus aureus represent major health and food industry problems. Bacteria have developed many strategies to resist the antibacterial activity of antibiotics, leading to multidrug resistance (MDR). The over-expression of drug efflux pumps and the formation of biofilms based on quorum sensing (QS) can contribute the emergence of MDR. For this reason, the development of novel effective compounds to overcome resistance is urgently needed. This study focused on the antibacterial activity of nine symmetrical selenoesters (Se-esters) containing additional functional groups including oxygen esters, ketones, and nitriles against Gram-positive and Gram-negative bacteria. Firstly, the minimum inhibitory concentrations of the compounds were determined. Secondly, the interaction of compounds with reference antibiotics was examined. The efflux pump (EP) inhibitory properties of the compounds were assessed using real-time fluorimetry. Finally, the anti-biofilm and quorum sensing inhibiting effects of selenocompounds were determined. The methylketone and methyloxycarbonyl selenoesters were the more effective antibacterials compared to cyano selenoesters. The methyloxycarbonyl selenoesters (Se-E2 and Se-E3) showed significant biofilm and efflux pump inhibition, and a methyloxycarbonyl selenoester (Se-E1) exerted strong QS inhibiting effect. Based on results selenoesters could be promising compounds to overcome bacterial MDR.

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“…Efflux pumps are highly conserved structures in pro-and eukaryotes. Comprehensive reviews have summarized a plethora of data describing interactions of a broad variety of agents with efflux pumps [238][239][240][241][242][243][244]. In general, nonsteroidal anti-inflammatory drugs (NSAIDS) and acetylsalicylic acid (aspirin ® ), its major metabolite salicylic acid, and acetaminophen (paracetamol ® ) in particular, interact not only with efflux pumps but exert pleiotropic antibacterial activities against bacteria many of which are equivocal [245][246][247][248][249].…”

Section: Efflux Pump Inhibitors and Non-steroidal Anti-inflammatory Dmentioning

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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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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Efflux pump inhibitors for bacterial pathogens

Cited by 268 publications

References 101 publications

An oxindole efflux inhibitor potentiates azoles and impairs virulence in the fungal pathogen Candida auris

An oxindole efflux inhibitor potentiates azoles and impairs virulence in the fungal pathogen Candida auris

Biofilm Eradication by Symmetrical Selenoesters for Food-Borne Pathogens

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

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