Skip to main content
SpringerLink
Log in

Deciphering the Role of β-Lactamase Inhibitors, Membrane Permeabilizers and Efflux Pump Inhibitors as Emerging Targets in Antibiotic Resistance

  • Review article
  • Published:
Indian Journal of Microbiology Aims and scope Submit manuscript

Abstract

Antimicrobial drugs have been noticed to have reduce activity effective due to upsurge witnessed in resistance of microbes. To deal with viewpoint of such a circumstance, we must seek ways to prevent it or atleast mitigate its effects in order to provide its activity against the microbes. Hence, novel antimicrobials are the one of the most promising solution for ending antimicrobial resistance. Furthermore, due to the less development of newer antimicrobials in recent years, the only way to combat microbial resistance are various synergistic approaches of exploring antimicrobial drug combinations. This combination's efficacy is due to a synergistic chemical that re-sensitizes the resistant microbial strain. It has been observed that classes of β-lactamases inhibitors, efflux pump inhibitors and membrane permeabilizers are of particular relevance, since they can break resistance to the most commonly used antimicrobials. This review explains the readers that how these synergistic combinations can help to reduce or eliminate the microbial resistance supported with clinical evidence.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Ali J, Rafiq QA, Ratcliffe E (2018) Antimicrobial resistance mechanisms and potential synthetic treatments. Future Sci OA 4:FSO290. doi: https://doi.org/10.4155/fsoa-2017-0109

  2. Reygaert C (2018) An overview of the antimicrobial resistance mechanisms of bacteria. AIMS Microbiol 4:482–501. https://doi.org/10.3934/microbiol.2018.3.482

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  3. Mulani MS, Kamble EE, Kumkar SN et al (2019) Emerging strategies to combat ESKAPE pathogens in the era of antimicrobial resistance: a review. Front Microbiol . https://doi.org/10.3389/fmicb.2019.00539

    Article  PubMed  PubMed Central  Google Scholar 

  4. Sg K, Adithan C, Harish B et al (2013) Antimicrobial resistance in India: a review. J Nat Sci Biol Med 4:286. https://doi.org/10.4103/0976-9668.116970

    Article  Google Scholar 

  5. Organization WH (2014) Antimicrobial resistance: global report on surveillance. World Health Organization

  6. Ganguly NK, Arora NK, Chandy SJ et al (2011) Rationalizing antibiotic use to limit antibiotic resistance in India. Indian J Med Res 134:281–294

    PubMed  Google Scholar 

  7. Chernov VM, Chernova OA, Mouzykantov AA et al (2019) Omics of antimicrobials and antimicrobial resistance. Expert Opin Drug Discov 14:455–468. https://doi.org/10.1080/17460441.2019.1588880

    Article  PubMed  CAS  Google Scholar 

  8. Kahn LH (2017) Antimicrobial resistance: a One Health perspective. Trans R Soc Trop Med Hyg 111:255–260. https://doi.org/10.1093/trstmh/trx050

    Article  PubMed  Google Scholar 

  9. Davies J, Davies D (2010) Origins and Evolution of Antibiotic Resistance. Microbiol Mol Biol Rev 74:417–433. https://doi.org/10.1128/MMBR.00016-10

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  10. Dixit A, Kumar N, Kumar S, Trigun V (2019) Antimicrobial resistance: progress in the decade since emergence of new Delhi metallo-β-lactamase in India. Indian J Community Med 44:4–8. https://doi.org/10.4103/ijcm.IJCM_217_18

    Article  PubMed  PubMed Central  Google Scholar 

  11. Laws M, Shaaban A, Rahman KM (2019) Antibiotic resistance breakers: current approaches and future directions. FEMS Microbiol Rev 43:490–516. https://doi.org/10.1093/femsre/fuz014

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  12. Tyers M, Wright GD (2019) Drug combinations: a strategy to extend the life of antibiotics in the 21st century. Nat Rev Microbiol 17:141–155. https://doi.org/10.1038/s41579-018-0141-x

    Article  PubMed  CAS  Google Scholar 

  13. Khilnani GC, Zirpe K, Hadda V et al (2019) Guidelines for antibiotic prescription in intensive care unit. Indian J Crit Care Med 23:S1–S63. https://doi.org/10.5005/jp-journals-10071-23101

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  14. Coates ARM, Hu Y, Holt J, Yeh P (2020) Antibiotic combination therapy against resistant bacterial infections: synergy, rejuvenation and resistance reduction. Expert Rev Anti Infect Ther 18:5–15. https://doi.org/10.1080/14787210.2020.1705155

    Article  PubMed  CAS  Google Scholar 

  15. Tamma PD, Cosgrove SE, Maragakis LL (2012) Combination therapy for treatment of infections with gram-negative bacteria. Clin Microbiol Rev 25:450–470. https://doi.org/10.1128/CMR.05041-11

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  16. Cheesman M, Ilanko A, Blonk B, Cock I (2017) Developing new antimicrobial therapies: are synergistic combinations of plant extracts/compounds with conventional antibiotics the solution? Pharmacogn Rev 11:57. https://doi.org/10.4103/phrev.phrev_21_17

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  17. Tooke CL, Hinchliffe P, Bragginton EC et al (2019) β-Lactamases and β-Lactamase Inhibitors in the 21st Century. J Mol Biol 431:3472–3500. https://doi.org/10.1016/j.jmb.2019.04.002

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  18. Kumarasamy KK, Toleman MA, Walsh TR et al (2010) Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study. Lancet Infect Dis 10:597–602. https://doi.org/10.1016/S1473-3099(10)70143-2

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  19. González-Bello C, Rodríguez D, Pernas M et al (2020) β-Lactamase inhibitors to restore the efficacy of antibiotics against superbugs. J Med Chem 63:1859–1881. https://doi.org/10.1021/acs.jmedchem.9b01279

    Article  PubMed  CAS  Google Scholar 

  20. Watkins RR, Papp-Wallace KM, Drawz SM, Bonomo RA (2013) Novel β-lactamase inhibitors: a therapeutic hope against the scourge of multidrug resistance. Front Microbiol. https://doi.org/10.3389/fmicb.2013.00392

    Article  PubMed  PubMed Central  Google Scholar 

  21. Papp-Wallace KM, Bonomo RA (2016) New β-Lactamase inhibitors in the clinic. Infect Dis Clin North Am 30:441–464. https://doi.org/10.1016/j.idc.2016.02.007

    Article  PubMed  PubMed Central  Google Scholar 

  22. Drawz SM, Bonomo RA (2010) Three decades of β-lactamase inhibitors. Clin Microbiol Rev 23:160–201. https://doi.org/10.1128/CMR.00037-09

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  23. Finlay J (2003) A review of the antimicrobial activity of clavulanate. J Antimicrob Chemother 52:18–23. https://doi.org/10.1093/jac/dkg286

    Article  PubMed  CAS  Google Scholar 

  24. White AR (2004) Augmentin(R) (amoxicillin/clavulanate) in the treatment of community-acquired respiratory tract infection: a review of the continuing development of an innovative antimicrobial agent. J Antimicrob Chemother 53:3i–20. https://doi.org/10.1093/jac/dkh050

    Article  CAS  Google Scholar 

  25. Lai C-C, Chen C-C, Lu Y-C et al (2018) Appropriate composites of cefoperazone–sulbactam against multidrug-resistant organisms. Infect Drug Resist 11:1441–1445. https://doi.org/10.2147/IDR.S175257

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  26. Drawz SM, Papp-Wallace KM, Bonomo RA (2014) New β-lactamase inhibitors: a therapeutic renaissance in an MDR world. Antimicrob Agents Chemother 58:1835–1846. https://doi.org/10.1128/AAC.00826-13

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  27. Farrell DJ, Sader HS, Flamm RK, Jones RN (2014) Ceftolozane/tazobactam activity tested against Gram-negative bacterial isolates from hospitalised patients with pneumonia in US and European medical centres (2012). Int J Antimicrob Agents 43:533–539. https://doi.org/10.1016/j.ijantimicag.2014.01.032

    Article  PubMed  CAS  Google Scholar 

  28. Crandon J, Nicolau D (2015) In vitro activity of cefepime/AAI101 and comparators against cefepime non-susceptible enterobacteriaceae. Pathogens 4:620–625. https://doi.org/10.3390/pathogens4030620

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  29. Crandon JL, Nicolau DP (2015) In vivo activities of simulated human doses of cefepime and cefepime-AAI101 against multidrug-resistant Gram-negative Enterobacteriaceae. Antimicrob Agents Chemother 59:2688–2694. https://doi.org/10.1128/AAC.00033-15

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  30. Sharma R, Park TE, Moy S (2016) Ceftazidime-avibactam: a novel cephalosporin/β-lactamase inhibitor combination for the treatment of resistant gram-negative organisms. Clin Ther 38:431–444. https://doi.org/10.1016/j.clinthera.2016.01.018

    Article  PubMed  CAS  Google Scholar 

  31. Castanheira M, Mills JC, Costello SE et al (2015) ceftazidime-avibactam activity tested against enterobacteriaceae isolates from U.S. hospitals (2011 to 2013) and characterization of β-lactamase-producing strains. Antimicrob Agents Chemother 59:3509–3517. https://doi.org/10.1128/AAC.00163-15

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  32. Vaara M (2019) Polymyxins and their potential next generation as therapeutic antibiotics. Front Microbiol. https://doi.org/10.3389/fmicb.2019.01689

    Article  PubMed  PubMed Central  Google Scholar 

  33. Schmid A, Wolfensberger A, Nemeth J et al (2019) Monotherapy versus combination therapy for multidrug-resistant gram-negative infections: systematic review and meta-analysis. Sci Rep 9:15290. https://doi.org/10.1038/s41598-019-51711-x

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  34. Vaara M (2019) Polymyxin derivatives that sensitize gram-negative bacteria to other antibiotics. Molecules 24:249. https://doi.org/10.3390/molecules24020249

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  35. Lin L, Nonejuie P, Munguia J et al (2015) Azithromycin synergizes with cationic antimicrobial peptides to exert bactericidal and therapeutic activity against highly multidrug-resistant gram-negative bacterial pathogens. EBioMedicine 2:690–698. https://doi.org/10.1016/j.ebiom.2015.05.021

    Article  PubMed  PubMed Central  Google Scholar 

  36. Sertcelik A, Baran I, Akinci E et al (2020) Synergistic activities of colistin combinations with meropenem, sulbactam, minocycline, disodium fosfomycin, or vancomycin against different clones of carbapenem-resistant acinetobacter baumannii strains. Microb Drug Resist 26:429–433. https://doi.org/10.1089/mdr.2019.0088

    Article  PubMed  CAS  Google Scholar 

  37. Vaara M (1992) Agents that increase the permeability of the outer membrane. Microbiol Rev 56:395–411. https://doi.org/10.1128/mr.56.3.395-411.1992

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  38. Vaara M, Siikanen O, Apajalahti J et al (2010) A novel polymyxin derivative that lacks the fatty acid tail and carries only three positive charges has strong synergism with agents excluded by the intact outer membrane. Antimicrob Agents Chemother 54:3341–3346. https://doi.org/10.1128/AAC.01439-09

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  39. Corbett D, Wise A, Langley T et al (2017) Potentiation of antibiotic activity by a novel cationic peptide: potency and spectrum of activity of SPR741. Antimicrob Agents Chemother. https://doi.org/10.1128/AAC.00200-17

    Article  PubMed  PubMed Central  Google Scholar 

  40. P Tegos, M Haynes, J Jacob Strouse et al (2011) Microbial Efflux Pump Inhibition: Tactics and Strategies. Curr Pharm Des 17:1291–1302. doi: https://doi.org/10.2174/138161211795703726

  41. Sharma A, Gupta V, Pathania R (2019) Efflux pump inhibitors for bacterial pathogens: from bench to bedside. Indian J Med Res 149:129. https://doi.org/10.4103/ijmr.IJMR_2079_17

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  42. Willers C, Wentzel JF, du Plessis LH et al (2017) Efflux as a mechanism of antimicrobial drug resistance in clinical relevant microorganisms: the role of efflux inhibitors. Expert Opin Ther Targets 21:23–36. https://doi.org/10.1080/14728222.2017.1265105

    Article  PubMed  CAS  Google Scholar 

  43. Zhao Y-J, Liu W-D, Shen Y-N et al (2019) The efflux pump inhibitor tetrandrine exhibits synergism with fluconazole or voriconazole against Candida parapsilosis. Mol Biol Rep 46:5867–5874. https://doi.org/10.1007/s11033-019-05020-1

    Article  PubMed  CAS  Google Scholar 

  44. Li S-X, Song Y-J, Jiang L et al (2017) Synergistic effects of tetrandrine with posaconazole against aspergillus fumigatus. Microb Drug Resist 23:674–681. https://doi.org/10.1089/mdr.2016.0217

    Article  PubMed  CAS  Google Scholar 

  45. Tariq A, Sana M, Shaheen A, et al (2019) Restraining the multidrug efflux transporter STY4874 of Salmonella Typhi by reserpine and plant extracts. Lett Appl Microbiol lam. 13196. doi: https://doi.org/10.1111/lam.13196

  46. Kumar A, Khan IA, Koul S et al (2008) Novel structural analogues of piperine as inhibitors of the NorA efflux pump of Staphylococcus aureus. J Antimicrob Chemother 61:1270–1276. https://doi.org/10.1093/jac/dkn088

    Article  PubMed  CAS  Google Scholar 

  47. Sharma S, Kumar M, Sharma S et al (2010) Piperine as an inhibitor of Rv1258c, a putative multidrug efflux pump of Mycobacterium tuberculosis. J Antimicrob Chemother 65:1694–1701. https://doi.org/10.1093/jac/dkq186

    Article  PubMed  CAS  Google Scholar 

  48. Stermitz FR, Lorenz P, Tawara JN et al (2000) Synergy in a medicinal plant: antimicrobial action of berberine potentiated by 5’-methoxyhydnocarpin, a multidrug pump inhibitor. Proc Natl Acad Sci 97:1433–1437. https://doi.org/10.1073/pnas.030540597

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  49. Stapleton PD, Shah S, Anderson JC et al (2004) Modulation of β-lactam resistance in Staphylococcus aureus by catechins and gallates. Int J Antimicrob Agents 23:462–467. https://doi.org/10.1016/j.ijantimicag.2003.09.027

    Article  PubMed  CAS  Google Scholar 

  50. Kanagaratnam R, Sheikh R, Alharbi F, Kwon DH (2017) An efflux pump (MexAB-OprM) of Pseudomonas aeruginosa is associated with antibacterial activity of Epigallocatechin-3-gallate (EGCG). Phytomedicine 36:194–200. https://doi.org/10.1016/j.phymed.2017.10.010

    Article  PubMed  CAS  Google Scholar 

Download references

Funding

This review did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Chemistry, Vivekanand Education Society’s College of Pharmacy, Chembur, Mumbai, 400074, India

    Nilesh Mhapankar

  2. Department of Pharmacology, SVKM’s Dr. Bhanuben Nanavati College of Pharmacy, V. M. Road, Vile Parle (W), Mumbai, India

    Aqsa Siddique, Gaurav Doshi & Angel Godad

  3. Department of Pharmaceutical Sciences and Technology Maharashtra, Institute of Chemical Technology, Mumbai, India

    Angel Godad

  4. Department of Pharmaceutical Chemistry, SVKM’s Dr. Bhanuben Nanavati College of Pharmacy, V. M. Road, Vile Parle (W), Mumbai, India

    Sandip Zine

Authors
  1. Nilesh Mhapankar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Aqsa Siddique
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gaurav Doshi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Angel Godad
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sandip Zine
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sandip Zine.

Ethics declarations

Conflict of interest:

The authors declare no conflict of interest.

Ethical approval

Not applicable since it is a review article.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 17 kb)

Supplementary file2 (DOCX 130 kb)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mhapankar, N., Siddique, A., Doshi, G. et al. Deciphering the Role of β-Lactamase Inhibitors, Membrane Permeabilizers and Efflux Pump Inhibitors as Emerging Targets in Antibiotic Resistance. Indian J Microbiol 62, 524–530 (2022). https://doi.org/10.1007/s12088-022-01045-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12088-022-01045-6

Keywords

Search

Navigation