ANT2681: SAR Studies Leading to the Identification of a Metallo-β-lactamase Inhibitor with Potential for Clinical Use in Combination with Meropenem for the Treatment of Infections Caused by NDM-Producing Enterobacteriaceae
Davies, D. T.; Leiris, S.; Sprynski, N.et al.
2020 • In ACS Infectious Diseases, 6 (9), p. 2419-2430
[en] The clinical effectiveness of the important β-lactam class of antibiotics is under threat by the emergence of resistance, mostly due to the production of acquired serine- (SBL) and metallo-β-lactamase (MBL) enzymes. To address this resistance issue, multiple β-lactam/β-lactamase inhibitor combinations have been successfully introduced into the clinic over the past several decades. However, all of those combinations contain SBL inhibitors and, as yet, there are no MBL inhibitors in clinical use. Consequently, there exists an unaddressed yet growing healthcare problem due to the rise in recent years of highly resistant strains which produce New Delhi metallo (NDM)-type metallo-carbapenemases. Previously, we reported the characterization of an advanced MBL inhibitor lead compound, ANT431. Herein, we discuss the completion of a lead optimization campaign culminating in the discovery of the preclinical candidate ANT2681, a potent NDM inhibitor with strong potential for clinical development.
Disciplines :
Microbiology
Author, co-author :
Davies, D. T.; 436 rue Pierre et Marie Curied, 31670 Labège, France
Leiris, S.; 436 rue Pierre et Marie Curied, 31670 Labège, France
Sprynski, N.; 436 rue Pierre et Marie Curied, 31670 Labège, France
Castandet, J.; 436 rue Pierre et Marie Curied, 31670 Labège, France
Lozano, C.; 436 rue Pierre et Marie Curied, 31670 Labège, France
Bousquet, J.; 436 rue Pierre et Marie Curied, 31670 Labège, France
Zalacain, M.; 436 rue Pierre et Marie Curied, 31670 Labège, France
Vasa, S.; Srinivas Vasa - GVK Biosciences Pvt. Ltd, Survey No. 125 and 126, IDA, Mallapur, Hyderabad-500 076, Telangana, India
Dasari, P. K.; Srinivas Vasa - GVK Biosciences Pvt. Ltd, Survey No. 125 and 126, IDA, Mallapur, Hyderabad-500 076, Telangana, India
Pattipati, R.; Srinivas Vasa - GVK Biosciences Pvt. Ltd, Survey No. 125 and 126, IDA, Mallapur, Hyderabad-500 076, Telangana, India
Vempala, N.; Srinivas Vasa - GVK Biosciences Pvt. Ltd, Survey No. 125 and 126, IDA, Mallapur, Hyderabad-500 076, Telangana, India
Gujjewar, S.; Srinivas Vasa - GVK Biosciences Pvt. Ltd, Survey No. 125 and 126, IDA, Mallapur, Hyderabad-500 076, Telangana, India
Godi, S.; Srinivas Vasa - GVK Biosciences Pvt. Ltd, Survey No. 125 and 126, IDA, Mallapur, Hyderabad-500 076, Telangana, India
Jallala, R.; Srinivas Vasa - GVK Biosciences Pvt. Ltd, Survey No. 125 and 126, IDA, Mallapur, Hyderabad-500 076, Telangana, India
Sathyap, R. R.; Srinivas Vasa - GVK Biosciences Pvt. Ltd, Survey No. 125 and 126, IDA, Mallapur, Hyderabad-500 076, Telangana, India
Darshanoju, N. A.; Srinivas Vasa - GVK Biosciences Pvt. Ltd, Survey No. 125 and 126, IDA, Mallapur, Hyderabad-500 076, Telangana, India
Ravu, V. R.; Srinivas Vasa - GVK Biosciences Pvt. Ltd, Survey No. 125 and 126, IDA, Mallapur, Hyderabad-500 076, Telangana, India
Juventhala, R. R.; Srinivas Vasa - GVK Biosciences Pvt. Ltd, Survey No. 125 and 126, IDA, Mallapur, Hyderabad-500 076, Telangana, India
Pottabathini, N.; Srinivas Vasa - GVK Biosciences Pvt. Ltd, Survey No. 125 and 126, IDA, Mallapur, Hyderabad-500 076, Telangana, India
Sharma, S.; Srinivas Vasa - GVK Biosciences Pvt. Ltd, Survey No. 125 and 126, IDA, Mallapur, Hyderabad-500 076, Telangana, India
Pothukanuri, S.; Srinivas Vasa - GVK Biosciences Pvt. Ltd, Survey No. 125 and 126, IDA, Mallapur, Hyderabad-500 076, Telangana, India
ANT2681: SAR Studies Leading to the Identification of a Metallo-β-lactamase Inhibitor with Potential for Clinical Use in Combination with Meropenem for the Treatment of Infections Caused by NDM-Producing Enterobacteriaceae
O'Neill, J. (2016) Review on Antimicrobial Resistance, Antimicrobial Resistance: Tackling a Crisis for the Health and Wealth of Nations. For this seminal review of antibacterial resistance, see https://amr-review.org/home.html (accessed June 6, 2019).
Bush, K. and Jacoby, G. A. (2010) Updated functional classification of beta-lactamases. Antimicrob. Agents Chemother. 54, 969-976, 10.1128/AAC.01009-09
Yin, D., Wu, S., Shi, Q., Dong, D., Zhu, D., and Hu, F. (2019) Results from the China Antimicrobial Surveillance Network (CHINET) in 2017 of the In Vitro Activities of Ceftazidime-Avibactam and Ceftolozane-Tazobactam against Clinical Isolates of Enterobacteriaceae and Pseudomonas aeuruginosa. Antimicrob. Agents Chemother. 63, e02431-18 10.1128/AAC.02431-18
Shen, Z., Gao, Q., Qin, J., Liu, Y., and Li, M. (2019) Emergence of an NDM-5-Producing Hypervirulent Klebsiella pneumoniae Sequence Type 35 Strain with Chromosomal Integration of an Integrative and Conjugative Element, ICE KP1. Antimicrob. Agents Chemother. 64, e01675-19 10.1128/AAC.01675-19
Bi, R., Kong, Z., Qian, H., Jiang, F., Kang, H., Gu, B., and Ma, P. (2018) High Prevalence of blaNDMVariants Among Carbapenem-Resistant Escherichia coli in Norther Jiangsu Province, China. Front. Microbiol. 9, 2704, 10.3389/fmicb.2018.02704
Castanheira, M., Deshpande, L. M., Mendes, R. E., Canton, R., Sader, H. S., and Jones, R. N. (2019) Variations in the Occurrence of Resistance Phenotypes and Carbapenemase Genes Among Enterobacteriaceae Isolates in 20 Years of the SENTRY Antimicrobial Surveillance Program. Open Forum Infect. Dis. 6 (Suppl. 1), S23-33, 10.1093/ofid/ofy347
Bush, K. and Bradford, P. A. (2019) Interplay between β-lactamases and new β-lactamase inhibitors. Nat. Rev. Microbiol. 17, 295, 10.1038/s41579-019-0159-8
Jean, S.-S., Gould, I. M., Lee, W.-S., and Hsueh, P.-R. (2019) New Drugs for Multi-Resistant Gram-Negative Organisms: Time for Stewardship. Drugs 79, 705-714, 10.1007/s40265-019-01112-1
Liu, B., Trout, R. E. L., Chu, G.-H., McGarry, D., Jackson, R. W., Hamrick, J. C., Daigle, D. M., Cusick, S. M., Pozzi, C., De Luca, F., Benvenuti, M., Mangani, S., Docquier, J.-D., Weiss, W. J., Pevier, D. C., Xerri, L., and Burns, C. J. (2020) Discovery of Taniborbactam (VNRX-5133): A Broad-Spectrum Serine-and Metallo-β-lactamase Inhibitor for Carbapenem-Resistant Bacterial Infections. J. Med. Chem. 63, 2789-2801, 10.1021/acs.jmedchem.9b01518
Kazmierczak, K., Hackel, M., and Sahn, D. (2018) In Vitro Activity of Cefepime in Combination with VNRX-5133 When Tested Against Cephalosporin and Carbapenem Resistant β-Lactamase Producing Gram-Negative Isolates, Poster P1544, ECMIDD2018.
Somboro, A. M., Sekyere, J. O., Amaoko, D. G., Essack, S. Y., and Bester, L. A. (2018) Diversity and Proliferation of Metallo-β-Lactamases; a Clarion Call for Clinically Effective Metallo-β-Lactamase Inhibitors. Appl. Environ. Microbiol. 84 (18), e00698 10.1128/AEM.00698-18
Everett, M., Sprynski, N., Coelho, A., Castandet, J., Bayet, M., Bougnon, J., Lozano, C., Davies, D. T., Leiris, S., Zalacain, M., Morrissey, I., Magnet, S., Holden, K., Warn, P., De Luca, F., Docquier, J.-D., and Lemonnier, M. (2018) Discovery of a Novel Metallo-β-Lactamase Inhibitor That Potentiates Meropenem Activity against Carbapenem-Resistant Enterobacteriaceae. Antimicrob. Agents Chemother. 62, e00074-18 10.1128/AAC.00074-18
Leiris, S., Coelho, A., Castandet, J., Bayet, M., Lozano, C., Bougnon, J., Bousquet, J., Everett, M., Lemonnier, M., Sprynski, N., Zalacain, M., Pallin, T. D., Cramp, M. C., Jennings, N., Raphy, G., Jones, M. W., Pattipati, R., Shankar, B., Sivasubrahmanyam, R., Soodhagani, A. K., Juventhala, R. R., Pottabathini, N., Pothukanuri, S., Benvenuti, M., Pozzi, C., Mangani, S., De Luca, F., Cerboni, G., Docquier, J. D., and Davies, D. T. (2019) SAR Studies Leading to the Identification of a Novel Series of Metallo-β-lactamase Inhibitors for the Treatment of Carbapenem-Resistant Enterobacteriaceae Infections That Display Efficacy in an Animal Infection Model. ACS Infect. Dis. 5, 131-140, 10.1021/acsinfecdis.8b00246
Ruiz-Castillo, P. and Buchwald, S. L. (2016) Applications of Palladium-Catalysed C-N Cross-Coupling Reactions. Chem. Rev. 116, 12564-12649, 10.1021/acs.chemrev.6b00512
Nizalapur, S., Kimyon, O., Yee, E., Ho, K., Berry, T., Manefield, M., Cranfield, C. G., Willcox, M., Black, D. S., and Kumar, N. (2017) Amphipathic guanidine-embedded glyoxamide-based peptidomimetics as novel antibacterial agents and biofilm disruptors. Org. Biomol. Chem. 15, 2033-2051, 10.1039/C7OB00053G
Congiu, C., Onnis, V., Deplano, A., Salvadori, S., Marconi, V., Maftei, D., Negri, L., Lattanzi, R., and Balboni, G. (2014) A new convenient synthetic method and preliminary pharmacological characterization of triazinediones as prokineticin receptor antagonists. Eur. J. Med. Chem. 81, 334, 10.1016/j.ejmech.2014.05.030
Harris, P. A., Marinis, J. M., Lich, J. D., Berger, S. B., Chirala, A., Cox, J. A., Eidam, P. A., Finger, J. N., Gough, P. J., Jeong, J. U., Kang, J., Kasparcova, V., Leister, L. K., Mahajan, M. K., Miller, G., Nagilla, R., Ouelette, M. T., Reilly, M. A., Rendina, A. R., Rivera, E. J., Sun, H. H., Thorpe, J. H., Totoritis, R. D., Wang, W., Wu, D., Zhang, D., Bertin, J., and Marquis, R. W. (2019) Identification of a RIP Kinase Inhibitor Clinical Candidate (GSK3145059) for the Treatment of Pancreatic Cancer. ACS Med. Chem. Lett. 10, 857-862, 10.1021/acsmedchemlett.9b00108
Richter, M. F., Drown, B. S., Riley, A. P., Garcia, A., Shirai, T., Svec, R. L., and Hergenrother, P. J. (2017) Predictive rules for compound accumulation yield a broad-spectrum antibiotic. Nature 545, 299-304, 10.1038/nature22308
Sun, Z., Hu, L., Sankaran, B., Prasad, B. V. V., and Palzkill, T. (2018) Differential active site requirements for NDM-1 β-lactamase hydrolysis of carbapenem versus penicillin and cephalosporin antibiotics. Nat. Commun. 9, 4524, 10.1038/s41467-018-06839-1
Zhang, H. M. and Hao, Q. (2011) Crystal structure of NDM-1 reveals a common β-lactam hydrolysis mechanism. FASEB J. 25, 2574-2582, 10.1096/fj.11-184036
Ishikawa, M. and Hashimoto, Y. (2011) Improvement in aqueous solubility in small molecule drug discovery programs by disruption of molecular planarity and symmetry. J. Med. Chem. 54, 1539-54, 10.1021/jm101356p
Dandekar, P. K., Maglio, D., Sutherland, C. A., Nightingale, C. H., and Nicolau, D. P. (2003) Pharmacokinetics of Meropenem 0.5 and 2G Every 8 h as a 3-h Infusion. Pharmacotherapy 23, 988-991, 10.1592/phco.23.8.988.32878
Lee, Y., Kim, J., and Trinh, S. (2019) Meropenem-Vaborbactam (VabomereTM): Another Option for Carbapenem-Resistant Enterobacteriaceae. Pharm. Ther. 44, 110-113
Yoshihiro, S., Nouda, H., Tada, E., Kohzuki, T., Kato, M., Okuda, T., and Fukasawa, M. (1992) Pharmacokinetics of Meropenem, a New Carbapenem Antibiotic. Chemotherapy 40 (Suppl. 1), 123-131, 10.11250/chemotherapy1953.40.Supplement1_123
Morinaga, Y., Yangihara, K., Nakamura, S., Kazuko, Y., Izumikawa, K., Seki, M., Kakeya, H., Yamamoto, Y., Yamade, Y., Kohno, S., and Makihara, S. (2008) In vivo efficacy and pharmacokinetics of tomopenem (CS-023), a novel carbapenem, against Pseudomonas aeruginosa in a murine chronic respiratory tract infection model. J. Antimicrob. Chemother. 62, 1326-1331, 10.1093/jac/dkn411
Efficacy studies were performed by: Evotec (UK) Ltd, Block 23, Alderly Park, Macclesfield, Cheshire, SK10 4TG, UK.
