Molecules that Inhibit Bacterial Resistance Enzymes

Liu, Yuan; Li, Ruichao; Xiao, Xia; Wang, Zhiqiang

doi:10.3390/molecules24010043

Cited by 41 publications

(19 citation statements)

References 202 publications

(217 reference statements)

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“…Coadministration with inhibitors of resistance represents a validated strategy to extend the therapeutically useful lifetime of antibiotics. 35 In this instance, our findings suggest that approaches that hinder metal ion access to a second zinc site represent one possible route to MCR inhibition. 36…”

Section: Discussionmentioning

confidence: 76%

Catalytic Mechanism of the Colistin Resistance Protein MCR-1

Suardíaz

Lythell²,

Hinchliffe³

et al. 2020

Preprint

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<div> <div> <div> <p>The mcr-1 gene encodes a membrane-bound Zn2+-metalloenzyme, MCR-1, which catalyzes phosphoethanolamine transfer onto bacterial lipid A, making bacteria resistant to colistin, a last-resort antibiotic. Mechanistic understanding of this process remains incomplete. Here, we investigate possible catalytic pathways using DFT and ab initio calculations on cluster models and identify a complete two-step reaction mechanism. The first step, formation of a covalent phosphointermediate via trans-fer of phosphoethanolamine from a membrane phospholipid donor to the acceptor Thr285, is rate-limiting and proceeds with a single Zn2+ ion. The second step, transfer of the phosphoethanolamine group to lipid A, requires an additional Zn2+. The calculations suggest the involment of the Zn2+ orbitals directly in the reaction is limited, with the second Zn2+ acting to bind incoming lipid A and direct phosphoethanolamine addition. The new level of mechanistic detail obtained here, which distinguishes these enzymes from other phosphotransferases, will aid in the development of inhibitors specific to MCR-1 and related bacterial phosphoethanolamine transferases. </p> </div> </div> </div>

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Section: Discussionmentioning

confidence: 76%

Catalytic Mechanism of the Colistin Resistance Protein MCR-1

Suardíaz

Lythell²,

Hinchliffe³

et al. 2020

Preprint

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“…As previously described, resistance enzymes impair antibiotic activity through multiple pathways, such as antibiotic hydrolysis or modification, or modification of antibiotic targets. Inhibition of enzyme-mediated drug resistance has been proven to be a clinically successful regimen to restore the activity of specific antibiotics 77 . The most successful examples are β-lactamase inhibitors (as reviewed in Ref.…”

Section: Drug Combinations Strategymentioning

confidence: 99%

Drug repurposing for next-generation combination therapies against multidrug-resistant bacteria

et al. 2021

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Antimicrobial resistance has been a global health challenge that threatens our ability to control and treat life-threatening bacterial infections. Despite ongoing efforts to identify new drugs or alternatives to antibiotics, no new classes of antibiotic or their alternatives have been clinically approved in the last three decades. A combination of antibiotics and non-antibiotic compounds that could inhibit bacterial resistance determinants or enhance antibiotic activity offers a sustainable and effective strategy to confront multidrug-resistant bacteria. In this review, we provide a brief overview of the co-evolution of antibiotic discovery and the development of bacterial resistance. We summarize drug-drug interactions and uncover the art of repurposing non-antibiotic drugs as potential antibiotic adjuvants, including discussing classification and mechanisms of action, as well as reporting novel screening platforms. A pathogen-by-pathogen approach is then proposed to highlight the critical value of drug repurposing and its therapeutic potential. Finally, general advantages, challenges and development trends of drug combination strategy are discussed.

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“… 16 In particular, inhibitors of resistance enzymes offer an alternative avenue to withstand this threat. 17 The combination of such inhibitors with clinically relevant antibiotics may effectively extend the lifetime of these antibacterial drugs and minimize the impact of the appearance of resistance. Medicinal plants are an extraordinary rich storehouse of bioactive secondary metabolites with a large spectrum of enzyme inhibitory potential.…”

Section: Introductionmentioning

confidence: 99%

ent-Beyerane Diterpenes as a Key Platform for the Development of ArnT-Mediated Colistin Resistance Inhibitors

et al. 2020

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Colistin is a last-resort antibiotic for the treatment of multidrug resistant Gram-negative bacterial infections. Recently, a natural ent -beyerene diterpene was identified as a promising inhibitor of the enzyme responsible for colistin resistance mediated by lipid A aminoarabinosylation in Gram-negative bacteria, namely, ArnT (undecaprenyl phosphate-alpha-4-amino-4-deoxy- l -arabinose arabinosyl transferase). Here, semisynthetic analogues of hit were designed, synthetized, and tested against colistin-resistant Pseudomonas aeruginosa strains including clinical isolates to exploit the versatility of the diterpene scaffold. Microbiological assays coupled with molecular modeling indicated that for a more efficient colistin adjuvant activity, likely resulting from inhibition of the ArnT activity by the selected compounds and therefore from their interaction with the catalytic site of ArnT, an ent -beyerane scaffold is required along with an oxalate-like group at C-18/C-19 or a sugar residue at C-19 to resemble L-Ara4N. The ent -beyerane skeleton is identified for the first time as a privileged scaffold for further cost-effective development of valuable colistin resistance inhibitors.

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Molecules that Inhibit Bacterial Resistance Enzymes

Cited by 41 publications

References 202 publications

Catalytic Mechanism of the Colistin Resistance Protein MCR-1

Catalytic Mechanism of the Colistin Resistance Protein MCR-1

Drug repurposing for next-generation combination therapies against multidrug-resistant bacteria

ent-Beyerane Diterpenes as a Key Platform for the Development of ArnT-Mediated Colistin Resistance Inhibitors

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