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Efflux Pump Inhibitors: An Update on the Search for New Antimicrobial Resistance Breakers

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 October 2021) | Viewed by 20199

Special Issue Editors

Dr. Stefano Sabatini

E-Mail Website
Guest Editor
Department of Pharmaceutical Sciences, Università degli Studi di Perugia, via del Liceo 1, 06123 Perugia, Italy
Interests: medicinal chemistry; rational drug design; antibacterial agents; antimicrobial resistance; drug-resistant pathogens; natural products; drug repurposing; antimicrobial resistance breakers; efflux pump inhibitors
Special Issues, Collections and Topics in MDPI journals
Dr. Tommaso Felicetti

E-Mail Website
Assistant Guest Editor
Department of Pharmaceutical Sciences, Università degli Studi di Perugia, Perugia, Italy
Interests: medicinal chemistry; rational drug design; antibacterial agents; antimicrobial resistance; drug repurposing; antimicrobial resistance breakers; efflux pump inhibitors; chemotherapy; organic synthesis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Considering the microbial promptness in achieving successful mechanisms to escape antibiotic activity towards new drugs, the use of non-antibiotic adjuvant molecules that target resistance mechanisms is a valid approach to recover drug sensitivity in resistant microorganisms. This fascinating idea, to “freeze” resistance, would allow the antibiotics for which resistance occurred to recover their activity, thereby renewing our armamentarium for fighting microbial infections. Efflux pumps, reducing intracellular drug concentrations to subinhibitory levels and permitting microorganisms to grow in the presence of routinely adopted therapeutic doses, play a nonspecific role in the early stages of antibiotic exposure, thereby allowing microorganisms to develop more specific and effective mechanisms of resistance. Therefore, the use of efflux pump inhibitors (EPIs) in combination with extruded drug may be a promising strategy in the development of effective antimicrobial treatments.

This Special Issue aims to highlight the recent medicinal chemistry research on new bacterial, mycobacterial, pathogenic fungi, and protozoa EPIs.

Prof. Dr. Stefano Sabatini
Dr. Tommaso Felicetti
Guest Editors

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Keywords

  • efflux pump inhibitors;
  • antimicrobial resistance breakers;
  • drug-resistant pathogens;
  • antimicrobial resistance;
  • major facilitator superfamily (MFS);
  • ATP-binding cassette superfamily (ABC);
  • resistance/nodulation/division family (RND);
  • Gram-positive;
  • Gram-negative;
  • mycobacteria;
  • fungi;
  • protozoa

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Published Papers (5 papers)

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Research

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15 pages, 4781 KiB  
Article
Berberine Derivatives as Pseudomonas aeruginosa MexXY-OprM Inhibitors: Activity and In Silico Insights
by Giorgia Giorgini, Gianmarco Mangiaterra, Nicholas Cedraro, Emiliano Laudadio, Giulia Sabbatini, Mattia Cantarini, Cristina Minnelli, Giovanna Mobbili, Emanuela Frangipani, Francesca Biavasco and Roberta Galeazzi
Molecules 2021, 26(21), 6644; https://doi.org/10.3390/molecules26216644 - 2 Nov 2021
Cited by 12 | Viewed by 2818
Abstract
The natural alkaloid berberine has been demonstrated to inhibit the Pseudomonas aeruginosa multidrug efflux system MexXY-OprM, which is responsible for tobramycin extrusion by binding the inner membrane transporter MexY. To find a structure with improved inhibitory activity, we compared by molecular dynamics investigations [...] Read more.
The natural alkaloid berberine has been demonstrated to inhibit the Pseudomonas aeruginosa multidrug efflux system MexXY-OprM, which is responsible for tobramycin extrusion by binding the inner membrane transporter MexY. To find a structure with improved inhibitory activity, we compared by molecular dynamics investigations the binding affinity of berberine and three aromatic substituents towards the three polymorphic sequences of MexY found in P. aeruginosa (PAO1, PA7, and PA14). The synergy of the combinations of berberine or berberine derivatives/tobramycin against the same strains was then evaluated by checkerboard and time-kill assays. The in silico analysis evidenced different binding modes depending on both the structure of the berberine derivative and the specific MexY polymorphism. In vitro assays showed an evident MIC reduction (32-fold and 16-fold, respectively) and a 2–3 log greater killing effect after 2 h of exposure to the combinations of 13-(2-methylbenzyl)- and 13-(4-methylbenzyl)-berberine with tobramycin against the tobramycin-resistant strain PA7, a milder synergy (a 4-fold MIC reduction) against PAO1 and PA14, and no synergy against the ΔmexXY strain K1525, confirming the MexY-specific binding and the computational results. These berberine derivatives could thus be considered new hit compounds to select more effective berberine substitutions and their common path of interaction with MexY as the starting point for the rational design of novel MexXY-OprM inhibitors. Full article
(This article belongs to the Special Issue Efflux Pump Inhibitors: An Update on the Search for New Antimicrobial Resistance Breakers)
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15 pages, 968 KiB  
Article
Evaluation of Benzaldehyde as an Antibiotic Modulator and Its Toxic Effect against Drosophila melanogaster
by Luiz Jardelino de Lacerda Neto, Andreza Guedes Barbosa Ramos, Thiago Sampaio de Freitas, Cristina Rodrigues dos Santos Barbosa, Dárcio Luiz de Sousa Júnior, Abolghasem Siyadatpanah, Morteza Nejat, Polrat Wilairatana, Henrique Douglas Melo Coutinho and Francisco Assis Bezerra da Cunha
Molecules 2021, 26(18), 5570; https://doi.org/10.3390/molecules26185570 - 13 Sep 2021
Cited by 15 | Viewed by 3071
Abstract
Products of natural origin remain important in the discovery of new bioactive molecules and are less damaging to the environment. Benzaldehyde is a product of the metabolism of plants, and similarly to oxygenated terpenes, it can have antibacterial activity against Staphylococcus aureus and [...] Read more.
Products of natural origin remain important in the discovery of new bioactive molecules and are less damaging to the environment. Benzaldehyde is a product of the metabolism of plants, and similarly to oxygenated terpenes, it can have antibacterial activity against Staphylococcus aureus and toxic action against Drosophila melanogaster; we aimed to verify these activities. The broth microdilution tests determined the minimum inhibitory concentration (MIC) of benzaldehyde alone and in association with antibiotics and ethidium bromide (EtBr). Toxicity against Drosophila melanogaster was determined by fumigation tests that measured lethality and damage to the locomotor system. The results indicated that there was an association of norfloxacin and ciprofloxacin with benzaldehyde, from 64 μg/mL to 32 μg/mL of ciprofloxacin in the strain K6028 and from 256 μg/mL to 128 μg/mL of norfloxacin in the strain 1199B; however, the associations were not able to interfere with the functioning of the tested efflux pumps. In addition, benzaldehyde had a toxic effect on flies. Thus, the results proved the ability of benzaldehyde to modulate quinolone antibiotics and its toxic effects on fruit flies, thus enabling further studies in this area. Full article
(This article belongs to the Special Issue Efflux Pump Inhibitors: An Update on the Search for New Antimicrobial Resistance Breakers)
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18 pages, 3582 KiB  
Article
Phenylpiperazine 5,5-Dimethylhydantoin Derivatives as First Synthetic Inhibitors of Msr(A) Efflux Pump in Staphylococcus epidermidis
by Karolina Witek, Gniewomir Latacz, Aneta Kaczor, Joanna Czekajewska, Ewa Żesławska, Anna Chudzik, Elżbieta Karczewska, Wojciech Nitek, Katarzyna Kieć-Kononowicz and Jadwiga Handzlik
Molecules 2020, 25(17), 3788; https://doi.org/10.3390/molecules25173788 - 20 Aug 2020
Cited by 7 | Viewed by 2683
Abstract
Herein, 15 phenylpiperazine 3-benzyl-5,5-dimethylhydantoin derivatives (1–15) were screened for modulatory activity towards Msr(A) efflux pump present in S. epidermidis bacteria. Synthesis, crystallographic analysis, biological studies in vitro and structure–activity relationship (SAR) analysis were performed. The efflux pump inhibitory (EPI) [...] Read more.
Herein, 15 phenylpiperazine 3-benzyl-5,5-dimethylhydantoin derivatives (1–15) were screened for modulatory activity towards Msr(A) efflux pump present in S. epidermidis bacteria. Synthesis, crystallographic analysis, biological studies in vitro and structure–activity relationship (SAR) analysis were performed. The efflux pump inhibitory (EPI) potency was determined by employing ethidium bromide accumulation assay in both Msr(A) efflux pump overexpressed (K/14/1345) and deficient (ATCC 12228) S. epidermidis strains. The series of compounds was also evaluated for the capacity to reduce the resistance of K/14/1345 strain to erythromycin, a known substrate of Msr(A). The study identified five strong modulators for Msr(A) in S. epidermidis. The 2,4-dichlorobenzyl-hydantoin derivative 9 was found as the most potent EPI, inhibiting the efflux activity in K/14/1345 at a concentration as low as 15.63 µM. Crystallography-supported SAR analysis indicated structural properties that may be responsible for the activity found. This study identified the first synthetic compounds able to inhibit Msr(A) efflux pump transporter in S. epidermidis. Thus, the hydantoin-derived molecules found can be an attractive group in search for antibiotic adjuvants acting via Msr(A) transporter. Full article
(This article belongs to the Special Issue Efflux Pump Inhibitors: An Update on the Search for New Antimicrobial Resistance Breakers)
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12 pages, 1379 KiB  
Article
Flavonoids as Novel Efflux Pump Inhibitors and Antimicrobials Against Both Environmental and Pathogenic Intracellular Mycobacterial Species
by Julia Solnier, Liam Martin, Sanjib Bhakta and Franz Bucar
Molecules 2020, 25(3), 734; https://doi.org/10.3390/molecules25030734 - 7 Feb 2020
Cited by 48 | Viewed by 6760
Abstract
Therapeutic treatment options for opportunistic non-tuberculous mycobacterial (NTM) infection and/or serious mycobacterial infections such as tuberculosis (TB) and leprosy are limited due to the spread of antimicrobial resistance mechanism. Plant-derived natural compounds as prospective efflux pump inhibitors may present a promising adjunct to [...] Read more.
Therapeutic treatment options for opportunistic non-tuberculous mycobacterial (NTM) infection and/or serious mycobacterial infections such as tuberculosis (TB) and leprosy are limited due to the spread of antimicrobial resistance mechanism. Plant-derived natural compounds as prospective efflux pump inhibitors may present a promising adjunct to conventional chemotherapy by enhancing mycobacterial susceptibility to antibiotics. This study served to evaluate the antimicrobial and resistance-modifying profile of a range of plant-derived flavonoids against the mycobacterial model strains: M. smegmatis, M. aurum, and M. bovis BCG. The minimum inhibitory concentrations (MICs) of the compounds against the mycobacterial strains were determined using both agar dilution and broth dilution assays, while their efflux inhibitory activity was investigated via an ethidium bromide-based fluorometric assay. All compounds were screened for their synergistic effects with ethidium bromide (EtBr) and rifampicin (RIF) against M. smegmatis. Skullcapflavone II (5,2′-dihydroxy-6,7,8,6′-tetramethoxyflavone, 1) exerted potent antimicrobial activity against M. aurum and M. bovis BCG and considerably increased the susceptibility of M. smegmatis to EtBr and RIF. Nobiletin (5,6,7,8,3′,4′-hexamethoxyflavone, 2) was determined to be the most potent efflux-inhibitor in M. aurum and M. smegmatis. However, a connection between strong modulatory and putative efflux activity of the compounds could not be observed. Nevertheless, the results highlight two polymethoxyflavones, skullcapflavone II and nobiletin, with potent antimycobacterial and antibiotic resistance modulating activities as valuable adjuvants in anti-mycobacterial therapies. Full article
(This article belongs to the Special Issue Efflux Pump Inhibitors: An Update on the Search for New Antimicrobial Resistance Breakers)
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Review

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27 pages, 3107 KiB  
Review
Microbial Efflux Pump Inhibitors: A Journey around Quinoline and Indole Derivatives
by Giada Cernicchi, Tommaso Felicetti and Stefano Sabatini
Molecules 2021, 26(22), 6996; https://doi.org/10.3390/molecules26226996 - 19 Nov 2021
Cited by 16 | Viewed by 3886
Abstract
Antimicrobial resistance (AMR) is a complex threat to human health and, to date, it represents a hot topic in drug discovery. The use of non-antibiotic molecules to block resistance mechanisms is a powerful alternative to the identification of new antibiotics. Bacterial efflux pumps [...] Read more.
Antimicrobial resistance (AMR) is a complex threat to human health and, to date, it represents a hot topic in drug discovery. The use of non-antibiotic molecules to block resistance mechanisms is a powerful alternative to the identification of new antibiotics. Bacterial efflux pumps exert the early step of AMR development, allowing the bacteria to grow in presence of sub-inhibitory drug concentration and develop more specific resistance mechanisms. Thus, efflux pump inhibitors (EPIs) offer a great opportunity to fight AMR, potentially restoring antibiotic activity. Based on our experience in designing and synthesizing novel EPIs, herein, we retrieved information around quinoline and indole derivatives reported in literature on this topic. Thus, our aim was to collect all data around these promising classes of EPIs in order to delineate a comprehensive structure–activity relationship (SAR) around each core for different microbes. With this review article, we aim to help future research in the field in the discovery of new microbial EPIs with improved activity and a better safety profile. Full article
(This article belongs to the Special Issue Efflux Pump Inhibitors: An Update on the Search for New Antimicrobial Resistance Breakers)
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