Ahmed A. Saleh & Ahmed A. J. Mahmood

Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, Iraq.

Received: June 19, 2023/ Revised: July 18, 2023/Accepted: July 25, 2023

(✉) Corresponding Author: ahmedsot@gmail.com

Abstract

Bacterial resistance is spreading internationally and poses a serious threat to humans. β-lactam resistance has enhanced to an uncontrolled rate due to many reasons. The most significant form of resistance is destruction of the ß-lactam ring by a bacterial enzyme named ß-lactamase enzyme which is essential for antibacterial activity. There are currently six β-lactamases inhibitors that can be used clinically in conjugation with the antibiotic in order to protect them from enzymatic attacks. They bind the β-lactamase enzyme thus the β-lactam antibiotic catches the transpeptidase (PBP) which has the responsibility of peptidoglycan synthesis and disables it thus causing cell wall lysis. However, in order to tackle the fast escalating ß-lactam resistance, additional research is needed in order to create novel drugs with broad-spectrum. Herein we represent the recently published works of the β-lactamases inhibitors. Until nowadays there are no clinically approved MBL inhibitors, Efforts should be put to discover and evaluate novel MBLi to impede the spread of pathogenic-resistant bacteria and minimize their global health impact. The scientists realize this fact and emphasize their effort toward MBL inhibitors.

Keywords:  Bacterial Resistance, β-lactam ring, β-lactamases Inhibitors.

References

Abodakpi, H., Wanger, A., & Tam, V. H. (2019). What the clinical microbiologist should know about pharmacokinetics/pharmacodynamics in the era of emerging multidrug resistance: focusing on β-lactam/β-lactamase inhibitor combinations. Clinics in Laboratory Medicine39(3), 473-485. https://doi.org/10.1016/j.cll.2019.05.006

Antipin R. L., Beshnova D. A., Petrov R. A., Shiryaeva A. S., Andreeva I. et al. (2017) Synthesis, SAR and molecular docking study of novel non-b-lactam inhibitors of TEM type b-lactamase. Bioorganic & Medicinal Chemistry Letters. http://dx.doi.org/10.1016/j.bmcl.2017.02.025.

Blizzard, T. A., Chen, H., Kim, S., Wu, J., Bodner, R., Gude, C., & Hammond, M. L. (2014). Discovery of MK-7655, a β-lactamase inhibitor for combination with Primaxin®. Bioorganic & medicinal chemistry letters24(3), 780-785. https://doi.org/10.1016/j.bmcl.2013.12.101

Bouza, A. A., Swanson, H. C., Smolen, K. A., VanDine, A. L., Taracila, M. A., Romagnoli, C., & Wallar, B. J. (2017). Structure-based analysis of boronic acids as inhibitors of Acinetobacter-derived cephalosporinase-7, a unique class C β-lactamase. ACS infectious diseases, 4(3), 325-336. https://doi.org/10.1021/acsinfecdis.7b00152

Brem, J., Cain R., Cahill S., McDonough M.A., Clifton I.J., et al. (2016) Structural basis of metallobeta- lactamase, serine-beta-lactamase and penicillinbinding protein inhibition by cyclic boronates. Nat. Commun. 7, 12406.

Bush, K., Bradford, P.A. Interplay between β-lactamases and new β-lactamase inhibitors.Nat Rev Microbiol 17, 295–306 (2019). https://doi.org/10.1038/s41579-019-0159-8

Cahill, S.T., Cain R., Wang D.Y., Lohans C.T., Wareham D.W., et al. (2017) Cyclic boronates inhibit all classes of β-lactamases. Antimicrobial Agents and Chemotherapy. April, Vol. 61, Issue 4, e02260-16 https:// doi.org/10.1128/AAC.02260-16.

Caselli, E., Fini, F., Introvigne, M. L., Stucchi, M., Taracila, M. A., Fish, E. R., & Prati, F. (2020). 1, 2, 3-Triazolylmethaneboronate: a structure activity relationship study of a class of β-lactamase inhibitors against Acinetobacter baumannii cephalosporinase. ACS infectious diseases, 6(7), 1965-1975. https://doi.org/10.1021/acsinfecdis.0c00254

Chen, F., Bai, M., Liu, W., Kong, H., Zhang, T., Yao, H., & Qin, S. (2021). H2dpa derivatives containing pentadentate ligands: An acyclic adjuvant potentiates meropenem activity in vitro and in vivo against metallo-β-lactamase-producing Enterobacterales. European Journal of Medicinal Chemistry224, 113702. https://doi.org/10.1016/j.ejmech.2021.113702

Chigan, J. Z., Li, J. Q., Ding, H. H., Xu, Y. S., Liu, L., Chen, C., & Yang, K. W. (2022). Hydroxamates as a potent skeleton for the development of metallo‐β‐lactamase inhibitors. Chemical Biology & Drug Design99(2), 362-372. https://doi.org/10.1111/cbdd.13990

Christoff, R. M., Murray, G. L., Kostoulias, X. P., Peleg, A. Y., & Abbott, B. M. (2017). Synthesis of novel 1, 2, 5-oxadiazoles and evaluation of action against Acinetobacter baumannii. Bioorganic & Medicinal Chemistry, 25(24), 6267-6272. https://doi.org/10.1016/j.bmc.2017.08.015

Cui, D. Y., Yang, Y., Bai, M. M., Han, J. X., Wang, C. C., Kong, H. T., … & Zhang, E. (2020). Systematic research of H2dedpa derivatives as potent inhibitors of New Delhi metallo-β-lactamase-1. Bioorganic Chemistry101, 103965. https://doi.org/10.1016/j.bioorg.2020.103965

Docquier, J. and Mangani S. (2018) An update on β-lactamase inhibitor discovery and development. Drug Resistance Updates, 36, 13–29 https://doi.org/10.1016/j.drup.2017.11.002

Ehmann, D. E., Jahić, H., Ross, P. L., Gu, R. F., Hu, J., Durand-Réville, T. F., & Fisher, S. L. (2013). Kinetics of avibactam inhibition against class A, C, and D β-lactamases. Journal of Biological Chemistry288(39), 27960-27971. https://doi.org/10.1074/jbc.M113.485979

Eidam, O., Romagnoli C., Dalmasso G., Barelier S., Caselli E., et al. (2012) Fragment-guided design of subnanomolar β-lactamase inhibitors active in vivo. Proc. Natl. Acad. Sci. U. S. A., 109, 17448–17453. http://dx.doi.org/10. 1073/pnas.1208337109.

Farley, A. J., Ermolovich, Y., Calvopiña, K., Rabe, P., Panduwawala, T., Brem, J., & Schofield, C. J. (2021). Structural Basis of Metallo-β-lactamase Inhibition by N-Sulfamoylpyrrole-2-carboxylates. ACS Infectious Diseases7(6), 1809-1817. https://doi.org/10.1021/acsinfecdis.1c00104

Gangadharappa, B. S., Sharath, R., Revanasiddappa, P. D., Chandramohan, V., Balasubramaniam, M., & Vardhineni, T. P. (2020). Structural insights of metallo-beta-lactamase revealed an effective way of inhibition of enzyme by natural inhibitors. Journal of Biomolecular Structure and Dynamics38(13), 3757-3771. https://doi.org/10.1080/07391102.2019.1667265

Gao, H., Li, J. Q., Kang, P. W., Chigan, J. Z., Wang, H., Liu, L., & Yang, K. W. (2021). N-acylhydrazones confer inhibitory efficacy against New Delhi metallo-β-lactamase-1. Bioorganic Chemistry114, 105138. https://doi.org/10.1016/j.bioorg.2021.105138

Ge, Y., Kang, P. W., Li, J. Q., Gao, H., Zhai, L., Sun, L. Y., … & Yang, K. W. (2021). Thiosemicarbazones exhibit inhibitory efficacy against New Delhi metallo-β-lactamase-1 (NDM-1). The Journal of Antibiotics74(9), 574-579. https://doi.org/10.1038/s41429-021-00440-3

Grigorenko, V.G., Andreeva I.P., Rubtsova M.Y., Deygen I.M., Antipin R.L., et al. (2016) Novel non-β-lactam inhibitor of β-lactamase TEM-171 based on acylated phenoxyaniline, Biochimie, 132, 45-53. doi: 10.1016/ j.biochi.2016.10.011.

Hinchliffe, P., Moreno, D. M., Rossi, M. A., Mojica, M. F., Martinez, V., Villamil, V., & Spencer, J. (2021). 2-Mercaptomethyl thiazolidines (MMTZS) inhibit all metallo-β-lactamase classes by maintaining a conserved binding mode. ACS Infectious Diseases7(9), 2697-2706. https://doi.org/10.1021/acsinfecdis.1c00194

Hirvonen, V. H., Spencer, J., & Van Der Kamp, M. W. (2021). Antimicrobial resistance conferred by OXA-48 β-lactamases: towards a detailed mechanistic understanding. Antimicrobial Agents and Chemotherapy65(6), 10-1128.https://doi.org/10.1128/AAC.00184-21

Ju, L. C., Cheng, Z., Fast, W., Bonomo, R. A., & Crowder, M. W. (2018). The continuing challenge of metallo-β-lactamase inhibition: mechanism matters. Trends in pharmacological sciences39(7), 635-647. https://doi.org/10.1016/j.tips.2018.03.007

Li, G. B., Abboud M.I., Brem J., Someya H., Lohans C.T., et al. (2017) NMR-filtered virtual screening leads to nonmetal chelating metallo-beta-lactamase inhibitors. Chem. Sci., 8, 928–937.

Li, J. Q., Gao, H., Zhai, L., Sun, L. Y., Chen, C., Chigan, J. Z., & Yang, K. W. (2021). Dipyridyl-substituted thiosemicarbazone as a potent broad-spectrum inhibitor of metallo-β-lactamases. Bioorganic & Medicinal Chemistry38, 116128. https://doi.org/10.1016/j.bmc.2021.116128

Li, J. Q., Sun, L. Y., Jiang, Z., Chen, C., Gao, H., Chigan, J. Z., & Yang, K. W. (2021). Diaryl-substituted thiosemicarbazone: A potent scaffold for the development of New Delhi metallo-β-lactamase-1 inhibitors. Bioorganic Chemistry107, 104576. https://doi.org/10.1016/j.bioorg.2020.104576

Li, R., Chen, X., Zhou, C., Dai, Q. Q., & Yang, L. (2022). Recent advances in β-lactamase inhibitor chemotypes and inhibition modes. European Journal of Medicinal Chemistry, 114677. https://doi.org/10.1016/j.ejmech.2022.114677

Linciano, P., Cendron, L., Gianquinto, E., Spyrakis, F., & Tondi, D. (2018). Ten years with New Delhi metallo-β-lactamase-1 (NDM-1): from structural insights to inhibitor design. ACS infectious diseases, 5(1), 9-34. https://doi.org/10.1021/acsinfecdis.8b00247

Liscio, J. L., Mahoney, M. V., & Hirsch, E. B. (2015). Ceftolozane/tazobactam and ceftazidime/avibactam: two novel β-lactam/β-lactamase inhibitor combination agents for the treatment of resistant Gram-negative bacterial infections. International journal of antimicrobial agents46(3), 266-271. https://doi.org/10.1016/j.ijantimicag.2015.05.003

Liu, S., Jing, L., Yu, Z. J., Wu, C., Zheng, Y., Zhang, E., … & Li, G. B. (2018). ((S)-3-Mercapto-2-methylpropanamido) acetic acid derivatives as metallo-β-lactamase inhibitors: synthesis, kinetic and crystallographic studies. European Journal of Medicinal Chemistry145, 649-660. https://doi.org/10.1016/j.ejmech.2018.01.032

Ma, G., Wang, S., Wu, K., Zhang, W., Ahmad, A., Hao, Q., … & Zhang, H. (2021). Structure-guided optimization of D-captopril for discovery of potent NDM-1 inhibitors. Bioorganic & Medicinal Chemistry29, 115902. https://doi.org/10.1016/j.bmc.2020.115902

Messasma, Z., Aggoun, D., Houchi, S., Ourari, A., Ouennoughi, Y., Keffous, F., & Mahdadi, R. (2021). Biological activities, DFT calculations and docking of imines tetradentates ligands, derived from salicylaldehydic compounds as metallo-beta-lactamase inhibitors. Journal of Molecular Structure, 1228, 129463. https://doi.org/10.1016/j.molstruc.2020.129463

Nelson, K., Rubio-Aparicio, D., Sun, D., Dudley, M., & Lomovskaya, O. (2020). In vitro activity of the ultrabroad-spectrum-beta-lactamase inhibitor QPX7728 against carbapenem-resistant Enterobacterales with varying intrinsic and acquired resistance mechanisms. Antimicrobial Agents and Chemotherapy64(8), e00757-20. https://doi.org/10.1128/aac.00757-20

Ness, S., Martin R., Kindler A.M., Paetzel M., Gold M., et al. (2000) Structure-based design guides the improved efficacy of deacylation transition state analogue inhibitors of TEM-1 β-lactamase. Biochemistry 39, 5312–5321. http://dx.doi.org/10.1021/bi992505b.

Parida, P., Bhowmick, S., Saha, A., & Islam, M. A. (2021). Insight into the screening of potential beta-lactamase inhibitors as anti-bacterial chemical agents through pharmacoinformatics study. Journal of Biomolecular Structure and Dynamics39(3), 923-942. https://doi.org/10.1080/07391102.2020.1720819

Reck, F., Bermingham A., Blais J., Casarez A., Colvin R., et al. (2019) IID572: A New Potentially Best-In-Class β‑Lactamase Inhibitor. ACS Infect. Dis., 5, 1045−105, DOI: 10.1021/acsinfecdis.9b00031

Rojas, L. J., Taracila M.A., Papp-Wallace K.M., Bethel C.R., Caselli E., et al. (2016) Boronic acid transition state inhibitors active against KPC and other class a betalactamases: structure–activity relationships as a guide to inhibitor design. Antimicrob. Agents Chemother., 60, 1751–1759.

Rotondo, C. M., & Wright, G. D. (2017). Inhibitors of metallo-β-lactamases. Current opinion in microbiology39, 96-105. https://doi.org/10.1016/j.mib.2017.10.026

Shaaban, M. M., Ragab, H. M., Akaji, K., McGeary, R. P., Bekhit, A. E. A., Hussein, W. M., … & Bekhit, A. A. (2020). Design, synthesis, biological evaluation and in silico studies of certain aryl sulfonyl hydrazones conjugated with 1, 3-diaryl pyrazoles as potent metallo-β-lactamase inhibitors. Bioorganic Chemistry, 105, 104386. https://doi.org/10.1016/j.bioorg.2020.104386

Shi, X. F., Wang, M. M., Huang, S. C., Han, J. X., Chu, W. C., Xiao, C., & Qin, S. (2019). H2depda: an acyclic adjuvant potentiates meropenem activity in vitro against metallo-β-lactamase-producing enterobacterales. European Journal of Medicinal Chemistry167, 367-376. https://doi.org/10.1016/j.ejmech.2019.01.083

Strynadka, N. C., Adachi H., Jensen S.E., Johns K., Sielecki A., et al. (1992) Molecular structure of the acyl-enzyme intermediate in β-lactam hydrolysis at 1.7 A resolution. Nature, 359, 700–705. http://dx.doi.org/10.1038/ 359700a0.

Taylor, D. M., Anglin, J., Hu, L., Wang, L., Sankaran, B., Wang, J., … & Palzkill, T. (2021). Unique Diacidic Fragments Inhibit the OXA-48 Carbapenemase and Enhance the Killing of Escherichia coli Producing OXA-48. ACS infectious diseases7(12), 3345-3354.https://doi.org/10.1021/acsinfecdis.1c00501

Taylor, D. M., Anglin, J., Park, S., Ucisik, M. N., Faver, J. C., Simmons, N., & Palzkill, T. (2020). Identifying oxacillinase-48 carbapenemase inhibitors using DNA-encoded chemical libraries. ACS infectious diseases6(5), 1214-1227. https://doi.org/10.1021/acsinfecdis.0c00015

Thomas, P. W., Cho, E. J., Bethel, C. R., Smisek, T., Ahn, Y. C., Schroeder, J. M., & Fast, W. (2022). Discovery of an effective small-molecule allosteric inhibitor of New Delhi metallo-β-lactamase (NDM). ACS Infectious Diseases8(4), 811-824. https://doi.org/10.1021/acsinfecdis.1c00577

Wang, M. M., Chu, W. C., Yang, Y., Yang, Q. Q., Qin, S. S., & Zhang, E. (2018). Dithiocarbamates: efficient metallo-β-lactamase inhibitors with good antibacterial activity when combined with meropenem. Bioorganic & Medicinal Chemistry Letters28(21), 3436-3440. https://doi.org/10.1016/j.bmcl.2018.09.028

Wong, D., & Van Duin, D. (2017). Novel beta-lactamase inhibitors: unlocking their potential in therapy. Drugs, 77(6), 615-628.DOI :https://doi.org/10.1007/s40265-017-0725-1

Yan, Y. H., Li, Z. F., Ning, X. L., Deng, J., Yu, J. L., Luo, Y., & Xiao, Y. C. (2021). Discovery of 3-aryl substituted benzoxaboroles as broad-spectrum inhibitors of serine-and metallo-β-lactamases. Bioorganic & Medicinal Chemistry Letters41, 127956. https://doi.org/10.1016/j.bmcl.2021.127956

Yu, Z. J., Liu, S., Zhou, S., Li, H., Yang, F., Yang, L. L., & Li, G. B. (2018). Virtual target screening reveals rosmarinic acid and salvianolic acid A inhibiting metallo-and serine-β-lactamases. Bioorganic & Medicinal Chemistry Letters28(6), 1037-1042. https://doi.org/10.1016/j.bmcl.2018.02.025

Yuan, K., & Ingleson, M. (2022). trans-Haloboration of o-Alkynyl Phenols Generates Halogenated Bicyclic-Boronates Relevant to Broad Spectrum Beta-Lactamase Inhibitors. https://doi.org/10.26434/chemrxiv-2022-9cq8q

Zhang, E., Wang, M. M., Huang, S. C., Xu, S. M., Cui, D. Y., Bo, Y. L., … & Qin, S. (2018). NOTA analogue: A first dithiocarbamate inhibitor of metallo-β-lactamases. Bioorganic & Medicinal Chemistry Letters28(2), 214-221. https://doi.org/10.1016/j.bmcl.2017.10.074

Zhao, B., Zhang, X., Yu, T., Liu, Y., Zhang, X., Yao, Y., & Qin, S. (2021). Discovery of thiosemicarbazone derivatives as effective New Delhi metallo-β-lactamase-1 (NDM-1) inhibitors against NDM-1 producing clinical isolates. Acta Pharmaceutica Sinica B11(1), 203-221. https://doi.org/10.1016/j.apsb.2020.07.005

Zhen, X., Lundborg, C. S., Sun, X., Hu, X., & Dong, H. (2019). Economic burden of antibiotic resistance in ESKAPE organisms: a systematic review. Antimicrobial Resistance & Infection Control, 8, 1-23.DOI: https://doi.org/10.1186/s13756-019-0590-7

How to cite this article

Saleh, A. A. & Mahmood, A. A. J. (2023). Novel β-lactamase inhibitors and the pursuit of MBL inhibitors to combat antibiotic-resistant bacteria: a review. Science Archives, Vol. 4(3), 199-207. https://doi.org/10.47587/SA.2023.4304

License                      Article Metadata

This work is licensed under a Creative Commons Attribution 4.0 International License.

[pdf_attachment file="1" name="View Details"]