Update on the Discovery of Efflux Pump Inhibitors against Critical Priority Gram-Negative Bacteria
Antimicrobial resistance (AMR) has become a major problem in public health leading to an estimated 4.95 million deaths in 2019. The selective pressure caused by the massive and repeated use of antibiotics has led to bacterial strains that are partially or even entirely resistant to known antibiotics...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-01-01
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| Series: | Antibiotics |
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| Online Access: | https://www.mdpi.com/2079-6382/12/1/180 |
| _version_ | 1797446917727191040 |
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| author | Nina Compagne Anais Vieira Da Cruz Reinke T. Müller Ruben C. Hartkoorn Marion Flipo Klaas M. Pos |
| author_facet | Nina Compagne Anais Vieira Da Cruz Reinke T. Müller Ruben C. Hartkoorn Marion Flipo Klaas M. Pos |
| author_sort | Nina Compagne |
| collection | DOAJ |
| description | Antimicrobial resistance (AMR) has become a major problem in public health leading to an estimated 4.95 million deaths in 2019. The selective pressure caused by the massive and repeated use of antibiotics has led to bacterial strains that are partially or even entirely resistant to known antibiotics. AMR is caused by several mechanisms, among which the (over)expression of multidrug efflux pumps plays a central role. Multidrug efflux pumps are transmembrane transporters, naturally expressed by Gram-negative bacteria, able to extrude and confer resistance to several classes of antibiotics. Targeting them would be an effective way to revive various options for treatment. Many efflux pump inhibitors (EPIs) have been described in the literature; however, none of them have entered clinical trials to date. This review presents eight families of EPIs active against <i>Escherichia coli</i> or <i>Pseudomonas aeruginosa</i>. Structure–activity relationships, chemical synthesis, <i>in vitro</i> and <i>in vivo</i> activities, and pharmacological properties are reported. Their binding sites and their mechanisms of action are also analyzed comparatively. |
| first_indexed | 2024-03-09T13:47:29Z |
| format | Article |
| id | doaj.art-c36548178e0f4e1bb0879082e17f1a6c |
| institution | Directory Open Access Journal |
| issn | 2079-6382 |
| language | English |
| last_indexed | 2024-03-09T13:47:29Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antibiotics |
| spelling | doaj.art-c36548178e0f4e1bb0879082e17f1a6c2023-11-30T20:56:52ZengMDPI AGAntibiotics2079-63822023-01-0112118010.3390/antibiotics12010180Update on the Discovery of Efflux Pump Inhibitors against Critical Priority Gram-Negative BacteriaNina Compagne0Anais Vieira Da Cruz1Reinke T. Müller2Ruben C. Hartkoorn3Marion Flipo4Klaas M. Pos5Univ. Lille, Inserm, Institut Pasteur de Lille, U1177—Drugs and Molecules for Living Systems, F-59000 Lille, FranceUniv. Lille, Inserm, Institut Pasteur de Lille, U1177—Drugs and Molecules for Living Systems, F-59000 Lille, FranceInstitute of Biochemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, GermanyUniv. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur Lille, U1019—UMR 9017—CIIL—Center for Infection and Immunity of Lille, F-59000 Lille, FranceUniv. Lille, Inserm, Institut Pasteur de Lille, U1177—Drugs and Molecules for Living Systems, F-59000 Lille, FranceInstitute of Biochemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, GermanyAntimicrobial resistance (AMR) has become a major problem in public health leading to an estimated 4.95 million deaths in 2019. The selective pressure caused by the massive and repeated use of antibiotics has led to bacterial strains that are partially or even entirely resistant to known antibiotics. AMR is caused by several mechanisms, among which the (over)expression of multidrug efflux pumps plays a central role. Multidrug efflux pumps are transmembrane transporters, naturally expressed by Gram-negative bacteria, able to extrude and confer resistance to several classes of antibiotics. Targeting them would be an effective way to revive various options for treatment. Many efflux pump inhibitors (EPIs) have been described in the literature; however, none of them have entered clinical trials to date. This review presents eight families of EPIs active against <i>Escherichia coli</i> or <i>Pseudomonas aeruginosa</i>. Structure–activity relationships, chemical synthesis, <i>in vitro</i> and <i>in vivo</i> activities, and pharmacological properties are reported. Their binding sites and their mechanisms of action are also analyzed comparatively.https://www.mdpi.com/2079-6382/12/1/180efflux pump inhibitorRND multidrug efflux pumpGram-negative bacteriaantimicrobial resistanceantibiotic resistance breakersAcrB |
| spellingShingle | Nina Compagne Anais Vieira Da Cruz Reinke T. Müller Ruben C. Hartkoorn Marion Flipo Klaas M. Pos Update on the Discovery of Efflux Pump Inhibitors against Critical Priority Gram-Negative Bacteria Antibiotics efflux pump inhibitor RND multidrug efflux pump Gram-negative bacteria antimicrobial resistance antibiotic resistance breakers AcrB |
| title | Update on the Discovery of Efflux Pump Inhibitors against Critical Priority Gram-Negative Bacteria |
| title_full | Update on the Discovery of Efflux Pump Inhibitors against Critical Priority Gram-Negative Bacteria |
| title_fullStr | Update on the Discovery of Efflux Pump Inhibitors against Critical Priority Gram-Negative Bacteria |
| title_full_unstemmed | Update on the Discovery of Efflux Pump Inhibitors against Critical Priority Gram-Negative Bacteria |
| title_short | Update on the Discovery of Efflux Pump Inhibitors against Critical Priority Gram-Negative Bacteria |
| title_sort | update on the discovery of efflux pump inhibitors against critical priority gram negative bacteria |
| topic | efflux pump inhibitor RND multidrug efflux pump Gram-negative bacteria antimicrobial resistance antibiotic resistance breakers AcrB |
| url | https://www.mdpi.com/2079-6382/12/1/180 |
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