Bacterial Drug Efflux Pump Inhibitors from Plants

Seukep, Armel Jackson; Fokoua-Maxime, Christophe Dongmo; Mbuntcha, Hélène; Chen, Guilin; Assob, Jules Clément Nguedia; Tenniswood, Martin; Sarker, Satyajit D.; Kuete, Victor; Chen, Guofang

doi:10.1007/978-981-16-3120-7_16

Cited by 3 publications

(5 citation statements)

References 185 publications

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“…Additionally, strains with heightened efflux pump expression and specific target mutations conferring resistance to levofloxacin (e.g., gyrA and parC) exhibit notable 32-to 64-fold MIC reductions in the presence of PAβN [215]. Despite extensive research and dedicated efforts over the course of the last two dec ades, the clinical approval of EPIs, especially small molecule inhibitors, remains elusive [147,217]. The clinical approval of EPIs continues to pose a significant challenge, primarily attributed to the intricate balance between their required activity concentrations and ob served toxicity effects, as well as their suboptimal pharmacokinetic properties and limited in vivo efficacies [43,50].…”

Section: The Perilous Dance: Unveiling the Clinical Relevance Of Mex ...mentioning

confidence: 99%

“…The toxicity issues associated with EPIs, which require high doses for significant activity, have contributed to the absence of ongoing trials [221]. Despite extensive research and dedicated efforts over the course of the last two decades, the clinical approval of EPIs, especially small molecule inhibitors, remains elusive [147,217]. The clinical approval of EPIs continues to pose a significant challenge, primarily attributed to the intricate balance between their required activity concentrations and observed toxicity effects, as well as their suboptimal pharmacokinetic properties and limited in vivo efficacies [43,50].…”

Section: The Perilous Dance: Unveiling the Clinical Relevance Of Mex ...mentioning

confidence: 99%

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The Art of War with Pseudomonas aeruginosa: Targeting Mex Efflux Pumps Directly to Strategically Enhance Antipseudomonal Drug Efficacy

Avakh,

Grant,

Cheesman

et al. 2023

Antibiotics

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Pseudomonas aeruginosa (P. aeruginosa) poses a grave clinical challenge due to its multidrug resistance (MDR) phenotype, leading to severe and life-threatening infections. This bacterium exhibits both intrinsic resistance to various antipseudomonal agents and acquired resistance against nearly all available antibiotics, contributing to its MDR phenotype. Multiple mechanisms, including enzyme production, loss of outer membrane proteins, target mutations, and multidrug efflux systems, contribute to its antimicrobial resistance. The clinical importance of addressing MDR in P. aeruginosa is paramount, and one pivotal determinant is the resistance-nodulation-division (RND) family of drug/proton antiporters, notably the Mex efflux pumps. These pumps function as crucial defenders, reinforcing the emergence of extensively drug-resistant (XDR) and pandrug-resistant (PDR) strains, which underscores the urgency of the situation. Overcoming this challenge necessitates the exploration and development of potent efflux pump inhibitors (EPIs) to restore the efficacy of existing antipseudomonal drugs. By effectively countering or bypassing efflux activities, EPIs hold tremendous potential for restoring the antibacterial activity against P. aeruginosa and other Gram-negative pathogens. This review focuses on concurrent MDR, highlighting the clinical significance of efflux pumps, particularly the Mex efflux pumps, in driving MDR. It explores promising EPIs and delves into the structural characteristics of the MexB subunit and its substrate binding sites.

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Section: The Perilous Dance: Unveiling the Clinical Relevance Of Mex ...mentioning

confidence: 99%

Section: The Perilous Dance: Unveiling the Clinical Relevance Of Mex ...mentioning

confidence: 99%

The Art of War with Pseudomonas aeruginosa: Targeting Mex Efflux Pumps Directly to Strategically Enhance Antipseudomonal Drug Efficacy

Avakh,

Grant,

Cheesman

et al. 2023

Antibiotics

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“…Several known inhibitors have been uncovered through computer analysis or extraction from plants. In recent years, extensive reviews have been published, emphasizing the diverse array of EPI agents unveiled so far originating from natural sources (plants and microbes), chemical synthesis, and drug repurposing of previously-approved drugs [ 8 , 18 , 111 , 112 , 113 , 114 ]. Some of the well-established EPIs from various sources ( Table 1 ) are described in the next sections.…”

Section: Strategies To Thwart Efflux Pump-mediated Bacterial Resistancementioning

confidence: 99%

“…Also, 11 displayed a synergistic effect with a fluoroquinolone (norfloxacin) against S. aureus [ 124 ]. A potential to interact synergistically has been reported with the homoisoflavonoid bonducellin ( 12 ), extracted from the root part of Caesalpinia digyna , in association with ethidium bromide to combat hard-to-treat Mycobacterium smegmatis [ 125 ]; these are not an exhaustive list of plant-derived EPIs, further naturally-occurring EPIs originating from plants have been extensively reviewed in some of our recent studies [ 8 , 18 ].…”

Section: Strategies To Thwart Efflux Pump-mediated Bacterial Resistancementioning

confidence: 99%

“…There is evidence that the inhibition of EPs is an intriguing approach as the supply of new antibiotics dries up. EPIs adhere to certain common inhibitory mechanisms of efflux and are being developed from a variety of synthetic and naturally-occurring sources [ 8 , 17 , 18 ]. Prospects for the use of EPIs include the possibility of preventing the occurrence of resistance, as well as the reuse of old antibiotics, which were previously discarded after losing efficiency owing to bacterial resistance.…”

Section: Introductionmentioning

confidence: 99%

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What Approaches to Thwart Bacterial Efflux Pumps-Mediated Resistance?

et al. 2022

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An effective response that combines prevention and treatment is still the most anticipated solution to the increasing incidence of antimicrobial resistance (AMR). As the phenomenon continues to evolve, AMR is driving an escalation of hard-to-treat infections and mortality rates. Over the years, bacteria have devised a variety of survival tactics to outwit the antibiotic's effects, yet given their great adaptability, unexpected mechanisms are still to be discovered. Over-expression of efflux pumps (EPs) constitutes the leading strategy of bacterial resistance, and it is also a primary driver in the establishment of multidrug resistance (MDR). Extensive efforts are being made to develop antibiotic resistance breakers (ARBs) with the ultimate goal of re-sensitizing bacteria to medications to which they have become unresponsive. EP inhibitors (EPIs) appear to be the principal group of ARBs used to impair the efflux system machinery. Due to the high toxicity of synthetic EPIs, there is a growing interest in natural, safe, and innocuous ones, whereby plant extracts emerge to be excellent candidates. Besides EPIs, further alternatives are being explored including the development of nanoparticle carriers, biologics, and phage therapy, among others. What roles do EPs play in the occurrence of MDR? What weapons do we have to thwart EP-mediated resistance? What are the obstacles to their development? These are some of the core questions addressed in the present review.

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New Hope in Microbial Multidrug Resistance

Ahire

Kshirsagar

2022

Community Acquir Infect

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From the last some decades, microbial multidrug resistance (MDR) has developed one of the big treats in the many drug therapy. Due to this effect, so many sectors were get affected including the pharmaceutical sector, animal husbandry sector as well as in some way the agriculture sector too. There are so many mechanisms were developed by the microbes to developed resistance towards the medicines consisting of the development of degrading enzymes, structural modification in the microbes which is responsible to bind the drug, as well as last but not the least developing many effluxes pumps to push drug molecules outside of the microbial cell. Many studies demonstrated that lots of antibiotics and anticancer agents are majorly get affected by efflux pumps present on the cell wall. These mechanisms are observed in many common microbes including gram-positive and gram-negative microbes. As a result, efflux pumps are to be taken on top priority for the minimization of multidrug resistance. Up to date lots of work is done regarding the permeation glycoprotein (P-gp) efflux pump inhibition but still, there is a need to explore some more innovative approaches towards MDR. In this current perspective, we have discussed the key points related to pre-existing and future prospects in this regard.

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Bacterial Drug Efflux Pump Inhibitors from Plants

Cited by 3 publications

References 185 publications

The Art of War with Pseudomonas aeruginosa: Targeting Mex Efflux Pumps Directly to Strategically Enhance Antipseudomonal Drug Efficacy

The Art of War with Pseudomonas aeruginosa: Targeting Mex Efflux Pumps Directly to Strategically Enhance Antipseudomonal Drug Efficacy

What Approaches to Thwart Bacterial Efflux Pumps-Mediated Resistance?

New Hope in Microbial Multidrug Resistance

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