Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 Nov 19;26(22):6996.
doi: 10.3390/molecules26226996.

Microbial Efflux Pump Inhibitors: A Journey around Quinoline and Indole Derivatives

Giada Cernicchi  1 , Tommaso Felicetti  1 , Stefano Sabatini  1
Affiliations
Review

Microbial Efflux Pump Inhibitors: A Journey around Quinoline and Indole Derivatives

Giada Cernicchi et al. Molecules. .

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 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.

Keywords: antibiotic resistance; antibiotic resistance breakers; antimicrobial resistance; efflux pump inhibitors; microbial efflux pumps.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Reference NorA EPI reserpine (RES) and NorA substrates ethidium bromide (EtBr), ciprofloxacin (CPX) and berberine. Blue color is used to highlight the indole portion present in reserpine.
Figure 2
Figure 2
From indoles to benzothiophene and benzofuran EPIs.
Figure 3
Figure 3
Indoles derivatives as NorA EPIs.
Figure 4
Figure 4
Benzothiophene derivatives as NorA EPIs.
Figure 5
Figure 5
N-1 substituted indole derivatives as NorA EPIs.
Figure 6
Figure 6
SAR of indole derivatives as NorA EPIs.
Figure 7
Figure 7
From flavone to quinoline nucleus.
Figure 8
Figure 8
C6-modified O-alkylamino quinolines 24–27 as NorA EPIs.
Figure 9
Figure 9
C-2 chlorothiophene-quinoline 28 and C-4 carboxy-quinoline 29 as NorA EPIs.
Figure 10
Figure 10
SAR of quinoline derivatives as NorA EPIs.
Figure 11
Figure 11
Reference AcrAB–TolC EPI PAβN and AcrAB–TolC substrates chloramphenicol (CAF), nalidixic acid (NA), norfloxacin (NFX), ofloxacin (OFX), oxacillin (OXA), cefepime (CEF), erythromycin (ERY), tetracycline (TET) and doxycycline (DOX).
Figure 12
Figure 12
Quinoline derivatives (30–35) reported as Gram-negative EPIs.
Figure 13
Figure 13
Quinoline derivatives (36–38) reported as Gram-negative EPIs.
Figure 14
Figure 14
Indole derivatives reported as Gram-negative EPIs.
Figure 15
Figure 15
Reference NTM EPIs verapamil (VP), chlorpromazine (CPZ), thioridazine (TDZ) and biochanin A (BChA) and NTM EP substrates azithromycin (AZT) and clarithromycin (CLA).
Figure 16
Figure 16
3-phenylquinolones as NTM EPIs.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. World Health Organization . Global Antimicrobial Resistance and Use Surveillance System (GLASS) Report: 2021. World Health Organization; Geneva, Switzerland: 2021.
    1. Miethke M., Pieroni M., Weber T., Brönstrup M., Hammann P., Halby L., Arimondo P.B., Glaser P., Aigle B., Bode H.B., et al. Towards the sustainable discovery and development of new antibiotics. Nat. Rev. Chem. 2021;5:726–749. doi: 10.1038/s41570-021-00313-1. - DOI - PMC - PubMed
    1. Kyriakides S. EU Action on Antimicrobial Resistance|Public Health. 2016. [(accessed on 16 November 2021)]. Available online: https://ec.europa.eu/health/antimicrobial-resistance/eu-action-on-antimi....
    1. Melander R.J., Melander C. The Challenge of Overcoming Antibiotic Resistance: An Adjuvant Approach? ACS Infect. Dis. 2017;3:559–563. doi: 10.1021/acsinfecdis.7b00071. - DOI - PMC - PubMed
    1. Brown D. Antibiotic resistance breakers: Can repurposed drugs fill the antibiotic discovery void? Nat. Rev. Drug Discov. 2015;14:821–832. doi: 10.1038/nrd4675. - DOI - PubMed

MeSH terms