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Antibiotics
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The Role of Efflux Pump Inhibitor in Bacterial Multidrug Resistance,...
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The Role of Efflux Pump Inhibitor in Bacterial Multidrug Resistance, 2nd Edition

A special issue of Antibiotics (ISSN 2079-6382).

Deadline for manuscript submissions: closed (31 January 2024) | Viewed by 12881

Special Issue Editors

Dr. Spengler Gabriella

E-Mail Website
Guest Editor
Department of Medical Microbiology and Immunobiology, University of Szeged, Dóm Square 10, H-6720 Szeged, Hungary
Interests: efflux systems of pathogenic bacteria; efflux pump inhibitors
Special Issues, Collections and Topics in MDPI journals
Dr. László Orosz

E-Mail Website
Co-Guest Editor
Department of Medical Microbiology, Albert Szent-Györgyi Medical School, University of Szeged, Semmelweis utca 6, 6725 Szeged, Hungary
Interests: clinical bacteriology; antibiotic resistance; multidrug efflux
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The first volume of the Special Issue “The Role of Efflux Pump Inhibitor in Bacterial Multidrug Resistance” was published in 2021. It was a successful issue that published 10 papers, and its succcess has encouraged us to open a second volume covering the same topic.

As a continuation of the Special Issue published in 2021, this second volume will also deliver an invaluable compendium of the latest approaches and challenges associated with the development of efflux pump inhibitor in bacterial multidrug resistance. Topics may include but are not limited to to following:

  • Multidrug resistance;
  • Multidrug efflux pumps;
  • Efflux pump inhibitors (EPIs);
  • Accumulation assays;
  • Efflux assays;
  • Fluorochromes;
  • Ethidium bromide;
  • Quorum sensing;
  • Biofilms.

Dr. Spengler Gabriella
Dr. László Orosz
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Antibiotics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • multidrug resistance
  • multidrug efflux pump
  • efflux pump inhibitor (EPI)
  • accumulation assay
  • efflux assay
  • fluorochromes
  • ethidium bromide
  • quorum sensing
  • biofilm

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Published Papers (5 papers)

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Research

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23 pages, 7037 KiB  
Article
Chalcogen-Varied Imidazolone Derivatives as Antibiotic Resistance Breakers in Staphylococcus aureus Strains
by Karolina Witek, Aneta Kaczor, Ewa Żesławska, Sabina Podlewska, Małgorzata Anna Marć, Kinga Czarnota-Łydka, Wojciech Nitek, Gniewomir Latacz, Waldemar Tejchman, Markus Bischoff, Claus Jacob and Jadwiga Handzlik
Antibiotics 2023, 12(11), 1618; https://doi.org/10.3390/antibiotics12111618 - 11 Nov 2023
Cited by 1 | Viewed by 1545
Abstract
In this study, a search for new therapeutic agents that may improve the antibacterial activity of conventional antibiotics and help to successfully overcome methicillin-resistant Staphylococcus aureus (MRSA) infections has been conducted. The purpose of this work was to extend the scope of our [...] Read more.
In this study, a search for new therapeutic agents that may improve the antibacterial activity of conventional antibiotics and help to successfully overcome methicillin-resistant Staphylococcus aureus (MRSA) infections has been conducted. The purpose of this work was to extend the scope of our preliminary studies and to evaluate the adjuvant potency of new derivatives in a set of S. aureus clinical isolates. The study confirmed the high efficacy of piperazine derivatives of 5-arylideneimidazol-4-one (7–9) tested previously, and it enabled the authors to identify even more efficient modulators of bacterial resistance among new analogs. The greatest capacity to enhance oxacillin activity was determined for 1-benzhydrylpiperazine 5-spirofluorenehydantoin derivative (13) which, at concentrations as low as 0.0625 mM, restores the effectiveness of β-lactam antibiotics against MRSA strains. In silico studies showed that the probable mechanism of action of 13 is related to the binding of the molecule with the allosteric site of PBP2a. Interestingly, thiazole derivatives tested were shown to act as both oxacillin and erythromycin conjugators in S. aureus isolates, suggesting a complex mode of action (i.e., influence on the Msr(A) efflux pump). This high enhancer activity indicates the high potential of imidazolones to become commercially available antibiotic adjuvants. Full article
(This article belongs to the Special Issue The Role of Efflux Pump Inhibitor in Bacterial Multidrug Resistance, 2nd Edition)
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15 pages, 1068 KiB  
Article
Antibacterial and Anti-Efflux Activities of Cinnamon Essential Oil against Pan and Extensive Drug-Resistant Pseudomonas aeruginosa Isolated from Human and Animal Sources
by Mohamed A. I. Abdelatti, Norhan K. Abd El-Aziz, El-sayed Y. M. El-Naenaeey, Ahmed M. Ammar, Nada K. Alharbi, Afaf Alharthi, Shadi A. Zakai and Adel Abdelkhalek
Antibiotics 2023, 12(10), 1514; https://doi.org/10.3390/antibiotics12101514 - 5 Oct 2023
Cited by 6 | Viewed by 2643
Abstract
Pseudomonas aeruginosa is notorious for its ability to develop a high level of resistance to antimicrobial agents. Resistance-nodulation-division (RND) efflux pumps could mediate drug resistance in P. aeruginosa. The present study aimed to evaluate the antibacterial and anti-efflux activities of cinnamon essential [...] Read more.
Pseudomonas aeruginosa is notorious for its ability to develop a high level of resistance to antimicrobial agents. Resistance-nodulation-division (RND) efflux pumps could mediate drug resistance in P. aeruginosa. The present study aimed to evaluate the antibacterial and anti-efflux activities of cinnamon essential oil either alone or combined with ciprofloxacin against drug resistant P. aeruginosa originated from human and animal sources. The results revealed that 73.91% of the examined samples were positive for P. aeruginosa; among them, 77.78% were of human source and 72.73% were recovered from animal samples. According to the antimicrobial resistance profile, 48.73% of the isolates were multidrug-resistant (MDR), 9.2% were extensive drug-resistant (XDR), and 0.84% were pan drug-resistant (PDR). The antimicrobial potential of cinnamon oil against eleven XDR and one PDR P. aeruginosa isolates was assessed by the agar well diffusion assay and broth microdilution technique. The results showed strong antibacterial activity of cinnamon oil against all tested P. aeruginosa isolates with inhibition zones’ diameters ranging from 34 to 50 mm. Moreover, the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values of cinnamon oil against P. aeruginosa isolates ranged from 0.0562–0.225 µg/mL and 0.1125–0.225 µg/mL, respectively. The cinnamon oil was further used to evaluate its anti-efflux activity against drug-resistant P. aeruginosa by phenotypic and genotypic assays. The cartwheel test revealed diminished efflux pump activity post cinnamon oil exposure by two-fold indicating its reasonable impact. Moreover, the real-time quantitative polymerase chain reaction (RT-qPCR) results demonstrated a significant (p < 0.05) decrease in the expression levels of MexA and MexB genes of P. aeruginosa isolates treated with cinnamon oil when compared to the non-treated ones (fold changes values ranged from 0.4204–0.7474 for MexA and 0.2793–0.4118 for MexB). In conclusion, we suggested the therapeutic use of cinnamon oil as a promising antibacterial and anti-efflux agent against drug-resistant P. aeruginosa. Full article
(This article belongs to the Special Issue The Role of Efflux Pump Inhibitor in Bacterial Multidrug Resistance, 2nd Edition)
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29 pages, 5844 KiB  
Article
Effect of Indole-Containing Pyrazino[2,1-b]quinazoline-3,6-diones in the Virulence of Resistant Bacteria
by Mariana C. Almeida, Nikoletta Szemerédi, Fernando Durães, Solida Long, Diana I. S. P. Resende, Paulo Martins da Costa, Madalena Pinto, Gabriella Spengler and Emília Sousa
Antibiotics 2023, 12(5), 922; https://doi.org/10.3390/antibiotics12050922 - 17 May 2023
Cited by 1 | Viewed by 2323
Abstract
Drug resistance is rising to alarming levels, constituting one of the major threats to global health. The overexpression of efflux pumps and the formation of biofilms constitute two of the most common resistance mechanisms, favoring the virulence of bacteria. Therefore, the research and [...] Read more.
Drug resistance is rising to alarming levels, constituting one of the major threats to global health. The overexpression of efflux pumps and the formation of biofilms constitute two of the most common resistance mechanisms, favoring the virulence of bacteria. Therefore, the research and development of effective antimicrobial agents that can also counteract resistance mechanisms are extremely important. Pyrazino[2,1-b]quinazoline-3,6-diones, from marine and terrestrial organisms and simpler synthetic analogues, were recently disclosed by us as having relevant antimicrobial properties. In this study, using a multi-step approach, it was possible to synthesize new pyrazino[2,1-b]quinazoline-3,6-diones focusing on compounds with fluorine substituents since, to the best of our knowledge, the synthesis of fluorinated fumiquinazoline derivatives had not been attempted before. The new synthesized derivatives were screened for antibacterial activity and, along with previously synthetized pyrazino[2,1-b]quinazoline-3,6-diones, were characterized for their antibiofilm and efflux-pump-inhibiting effects against representative bacterial species and relevant resistant clinical strains. Several compounds showed relevant antibacterial activity against the tested Gram-positive bacterial species with MIC values in the range of 12.5–77 μM. Furthermore, some derivatives showed promising results as antibiofilm agents in a crystal violet assay. The results of the ethidium bromide accumulation assay suggested that some compounds could potentially inhibit bacterial efflux pumps. Full article
(This article belongs to the Special Issue The Role of Efflux Pump Inhibitor in Bacterial Multidrug Resistance, 2nd Edition)
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Review

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30 pages, 1877 KiB  
Review
Repositioning of HMG-CoA Reductase Inhibitors as Adjuvants in the Modulation of Efflux Pump-Mediated Bacterial and Tumor Resistance
by Zsuzsanna Schelz, Hiba F. Muddather and István Zupkó
Antibiotics 2023, 12(9), 1468; https://doi.org/10.3390/antibiotics12091468 - 20 Sep 2023
Cited by 5 | Viewed by 2136
Abstract
Efflux pump (EP)-mediated multidrug resistance (MDR) seems ubiquitous in bacterial infections and neoplastic diseases. The diversity and lack of specificity of these efflux mechanisms raise a great obstacle in developing drugs that modulate efflux pumps. Since developing novel chemotherapeutic drugs requires large investments, [...] Read more.
Efflux pump (EP)-mediated multidrug resistance (MDR) seems ubiquitous in bacterial infections and neoplastic diseases. The diversity and lack of specificity of these efflux mechanisms raise a great obstacle in developing drugs that modulate efflux pumps. Since developing novel chemotherapeutic drugs requires large investments, drug repurposing offers a new approach that can provide alternatives as adjuvants in treating resistant microbial infections and progressive cancerous diseases. Hydroxy-methyl-glutaryl coenzyme-A (HMG-CoA) reductase inhibitors, also known as statins, are promising agents in this respect. Originally, statins were used in the therapy of dyslipidemia and for the prevention of cardiovascular diseases; however, extensive research has recently been performed to elucidate the functions of statins in bacterial infections and cancers. The mevalonate pathway is essential in the posttranslational modification of proteins related to vital eukaryotic cell functions. In this article, a comparative review is given about the possible role of HMG-CoA reductase inhibitors in managing diseases of bacterial and neoplastic origin. Molecular research and clinical studies have proven the justification of statins in this field. Further well-designed clinical trials are urged to clarify the significance of the contribution of statins to the lower risk of disease progression in bacterial infections and cancerous diseases. Full article
(This article belongs to the Special Issue The Role of Efflux Pump Inhibitor in Bacterial Multidrug Resistance, 2nd Edition)
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18 pages, 2122 KiB  
Review
Repurposing Antidepressants and Phenothiazine Antipsychotics as Efflux Pump Inhibitors in Cancer and Infectious Diseases
by Bálint Rácz and Gabriella Spengler
Antibiotics 2023, 12(1), 137; https://doi.org/10.3390/antibiotics12010137 - 10 Jan 2023
Cited by 17 | Viewed by 3400
Abstract
Multidrug resistance (MDR) is a major obstacle in the therapy of infectious diseases and cancer. One of the major mechanisms of MDR is the overexpression of efflux pumps (EPs) that are responsible for extruding antimicrobial and anticancer agents. EPs have additional roles of [...] Read more.
Multidrug resistance (MDR) is a major obstacle in the therapy of infectious diseases and cancer. One of the major mechanisms of MDR is the overexpression of efflux pumps (EPs) that are responsible for extruding antimicrobial and anticancer agents. EPs have additional roles of detoxification that may aid the development of bacterial infection and the progression of cancer. Therefore, targeting EPs may be an attractive strategy to treat bacterial infections and cancer. The development and discovery of a new drug require a long timeline and may come with high development costs. A potential alternative to reduce the time and costs of drug development is to repurpose already existing drugs. Antidepressants and antipsychotic agents are widely used in clinical practice in the treatment of psychiatric disorders and some somatic diseases. Antidepressants and antipsychotics have demonstrated various beneficial activities that may be utilized in the treatment of infections and cancer. This review aims to provide a brief overview of antibacterial and anticancer effects of selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs) and phenothiazine antipsychotics, while focusing on EPs. However, it should be noted that the antimicrobial activity of a traditionally non-antibiotic drug may have clinical implications regarding dysbiosis and bacterial MDR. Full article
(This article belongs to the Special Issue The Role of Efflux Pump Inhibitor in Bacterial Multidrug Resistance, 2nd Edition)
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