Novel β-lactamase inhibitors: A therapeutic hope against the scourge of multidrug resistance

Frontiers in Microbiology

Volumn 4, Issue DEC, 2013, Pages

  Watkins, Richard R ^a,b   Papp Wallace, Krisztina M ^c,d   Drawz, Sarah M ^e   Bonomo, Robert A ^c,d  

^a Northeastern Ohio Medical University   (United States)

^b AKRON GENERAL MEDICAL CENTER   (United States)

^c LOUIS STOKES CLEVELAND VA MEDICAL CENTER   (United States)

^d CASE WESTERN RESERVE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^e UNIVERSITY OF MINNESOTA MEDICAL SCHOOL   (United States)

Author keywords

Antibiotic resistance; lactamase inhibitors

Indexed keywords

1 ETHYLIDENE 1,2,5,6,7,8,8A,8B OCTAHYDRO 5 METHOXY 2 OXOAZETO[2,1 A]ISOINDOLE 4 CARBOXYLIC ACID; 3 [[2 (2 AMINO 4 THIAZOLYL) 2 [[(1,4 DIHYDRO 1,5 DIHYDROXY 4 OXO 2 PYRIDINYL)METHOXY]IMINO]ACETYL]AMINO] 4 METHYL 2 OXO 1 AZETIDINESULFONIC ACID; 4,7 DICHLORO 1 BENZOTHIEN 2 YL SULFONYLAMINOMETHYL BA; AMOXICILLIN PLUS CLAVULANIC ACID; AVIBACTAM; AZTREONAM; BAL 29880; BAL 30072; BAL 30376; BETA LACTAMASE INHIBITOR; BIAPENEM; CEFTAROLINE; CEFTAZIDIME; CEFTOLOZANE; CEPHALOSPORIN; CXA 201; CXA 202; DIAZABICYCLOOCTANE; METRONIDAZOLE; MK 7655; OXA 24; OXA 40; OXA 48; PIPERACILLIN PLUS TAZOBACTAM; RAZUPENEM; RPX 2003; RPX 7009; S 649266; SULTAMICILLIN; TAZOBACTAM; TIMENTIN; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ABDOMINAL INFECTION; ANTIBACTERIAL ACTIVITY; CLINICAL PRACTICE; DEACYLATION; DIABETIC FOOT; HUMAN; LUNG INFECTION; MATHEMATICAL MODEL; MINIMUM INHIBITORY CONCENTRATION; MULTIDRUG RESISTANCE; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); REVIEW; URINARY TRACT INFECTION;

EID: 84892143221     PISSN: None     EISSN: 1664302X     Source Type: Journal    
DOI: 10.3389/fmicb.2013.00392     Document Type: Review

References (63)

1. Ambler, R. P. (1980). The structure of β-lactamases. Philos. Trans. R. Soc. Lond. B Biol. Sci. 289, 321-331. doi: 10.1098/rstb.1980.0049.
2. Babini, G. S., Yuan, M., and Livermore, D. M. (1998). Interactions of β-lactamases with sanfetrinem (GV 104326) compared to those with imipenem and with oral β-lactams. Antimicrob. Agents Chemother. 42, 1168-1175.
3. Bassetti, M., Ginocchio, F., and Mikulska, M. (2011). New treatment options against Gram-negative organisms. Crit. Care 15, 215. doi: 10.1186/cc9997.
4. Bou, G., Santillana, E., Sheri, A., Beceiro, A., Sampson, J. M., Kalp, M., et al. (2010). Design, synthesis, and crystal structures of 6-alkylidene-2'-substituted penicillanic acid sulfones as potent inhibitors of Acinetobacter baumannii OXA-24 carbapenemase. J. Am. Chem. Soc. 132, 13320-13331. doi: 10.1021/ja104092z.
5. Boucher, H. W., Talbot, G. H., Benjamin, D. K. Jr., Bradley, J., Guidos, R. J., Jones, R. N., et al. (2013). 10 x '20 Progress-development of new drugs active against gram-negative bacilli: an update from the Infectious Diseases Society of America. Clin. Infect. Dis. 56, 1685-1694. doi: 10.1093/cid/cit152.
6. Bush, K. (2012). Improving known classes of antibiotics: an optimistic approach for the future. Curr. Opin. Pharmacol. 12, 527-534. doi: 10.1016/j.coph.2012.06.003.
7. Bush, K., and Jacoby, G. A. (2010). Updated functional classification of β-lactamases. Antimicrob. Agents Chemother. 54, 969-976. doi: 10.1128/AAC.01009-09.
8. Bush, K., and Macielag, M. J. (2010). New β-lactam antibiotics and β-lactamase inhibitors. Expert Opin. Ther. Pat. 20, 1277-1293. doi: 10.1517/13543776.2010.515588.
9. Castanheira, M., Becker, H., Rhomberg, P., and Jones, R. (2012a). "Pre-clinical evaluation of a carbapenem/β-lactamase inhibitor combination (RPX2003/RPX7009) tested against serine-carbapenemase-producing pathogens, abstr. F-856," in Interscience Conference on Antimicrobial Agents and Chemotherapy (San Francisco, CA).
10. Castanheira, M., Sader, H. S., Farrell, D. J., Mendes, R. E., and Jones, R. N. (2012b). Activity of ceftaroline-avibactam tested against Gram-negative organism populations, including strains expressing one or more β-lactamases and methicillin-resistant Staphylococcus aureus carrying various staphylococcal cassette chromosome mec types. Antimicrob. Agents Chemother. 56, 4779-4785. doi: 10.1128/AAC.00817-12.
11. Chen, Y., McReynolds, A., and Shoichet, B. K. (2009). Re-examining the role of Lys67 in class C β-lactamase catalysis. Protein Sci. 18, 662-669. doi: 10.1002/pro.60.
12. Chen, Y., Minasov, G., Roth, T. A., Prati, F., and Shoichet, B. K. (2006). The deacylation mechanism of AmpC β-lactamase at ultrahigh resolution. J. Am. Chem. Soc. 128, 2970-2976. doi: 10.1021/ja056806m.
13. Citron, D. M., Tyrrell, K. L., Merriam, V., and Goldstein, E. J. (2011). In vitro activity of ceftazidime-NXL104 against 396 strains of β-lactamase-producing anaerobes. Antimicrob. Agents Chemother. 55, 3616-3620. doi: 10.1128/AAC.01682-10.
14. Coleman, K. (2011). Diazabicyclooctanes (DBOs): a potent new class of non-β-lactam β-lactamase inhibitors. Curr. Opin. Microbiol. 14, 550-555. doi: 10.1016/j.mib.2011.07.026.
15. Crandon, J. L., Schuck, V. J., Banevicius, M. A., Beaudoin, M. E., Nichols, W. W., Tanudra, M. A., et al. (2012). Comparative in vitro and in vivo efficacies of human simulated doses of ceftazidime and ceftazidime-avibactam against Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 56, 6137-6146. doi: 10.1128/AAC.00851-12.
16. Drawz, S. M., Babic, M., Bethel, C. R., Taracila, M., Distler, A. M., Ori, C., et al. (2010a). Inhibition of the class C β-lactamase from Acinetobacter spp.: insights into effective inhibitor design. Biochemistry 49, 329-340. doi: 10.1021/bi9015988.
17. Drawz, S. M., Bethel, C. R., Doppalapudi, V. R., Sheri, A., Pagadala, S. R., Hujer, A. M., et al. (2010b). Penicillin sulfone inhibitors of class D β-lactamases. Antimicrob. Agents Chemother. 54, 1414-1424. doi: 10.1128/AAC.00743-09.
18. Drawz, S. M., and Bonomo, R. A. (2010). Three decades of β-lactamase inhibitors. Clin. Microbiol. Rev. 23, 160-201. doi: 10.1128/CMR.00037-09.
19. Dubus, A., Normark, S., Kania, M., and Page, M. G. (1995). Role of asparagine 152 in catalysis of β-lactam hydrolysis by Escherichia coli AmpC β-lactamase studied by site-directed mutagenesis. Biochemistry 34, 7757-7764. doi: 10.1021/bi00023a023.
20. Ehmann, D. E., Jahic, H., Ross, P. L., Gu, R. F., Hu, J., Kern, G., et al. (2012). Avibactam is a covalent, reversible, non-β-lactam β-lactamase inhibitor. Proc. Natl. Acad. Sci. U.S.A. 109, 11663-11668. doi: 10.1073/pnas.1205073109.
21. Fisher, J. F., and Mobashery, S. (2009). Three decades of the class A β-lactamase acyl-enzyme. Curr. Protein Pept. Sci. 10, 401-407. doi: 10.2174/138920309789351967.
22. Garau, G., Bebrone, C., Anne, C., Galleni, M., Frere, J. M., and Dideberg, O. (2005). A metallo-β-lactamase enzyme in action: crystal structures of the monozinc carbapenemase CphA and its complex with biapenem. J. Mol. Biol. 345, 785-795. doi: 10.1016/j.jmb.2004.10.070.
23. Gatti, D. L. (2012). Biapenem inactivation by B2 metallo β-lactamases: energy landscape of the post-hydrolysis reactions. PLoS ONE 7:e30079. doi: 10.1371/journal.pone.0030079.
24. Goldstein, E. J., Citron, D. M., Merriam, C. V., and Tyrrell, K. L. (2013a). Comparative in vitro activity of ceftaroline, ceftaroline-avibactam, and other antimicrobial agents against aerobic and anaerobic bacteria cultured from infected diabetic foot wounds. Diagn. Microbiol. Infect. Dis. 76, 347-351. doi: 10.1016/j.diagmicrobio.2013.03.019.
25. Goldstein, E. J., Citron, D. M., Tyrrell, K. L., and Merriam, C. V. (2013b). In vitro activity of Biapenem plus RPX7009, a carbapenem combined with a serine β-lactamase inhibitor, against anaerobic bacteria. Antimicrob. Agents Chemother. 57, 2620-2630. doi: 10.1128/AAC.02418-12.
26. Hecker, S., Reddy, K., Totrov, M., Hirst, G., Sabet, M., Tarazi, Z., et al. (2012). "Discovery of RPX7009, a broad-spectrum β-lactamase inhibitor with utility vs. class A serine carbapenemase, abstr F-848," in Interscience Conference on Antimicrobial Agents and Chemotherapy (San Francisco, CA).
27. Heinz, U., Bauer, R., Wommer, S., Meyer-Klaucke, W., Papamichaels, C., Bateson, J., et al. (2003). Coordination geometries of metal ions in d-or l-captopril-inhibited metallo-β-lactamases. J. Biol. Chem. 278, 20659-20666. doi: 10.1074/jbc.M212581200.
28. Higgins, P. G., Stefanik, D., Page, M. G., Hackel, M., and Seifert, H. (2012). In vitro activity of the siderophore monosulfactam BAL30072 against meropenem-non-susceptible Acinetobacter baumannii. J. Antimicrob. Chemother. 67, 1167-1169. doi: 10.1093/jac/dks009.
29. Hirsch, E. B., Ledesma, K. R., Chang, K. T., Schwartz, M. S., Motyl, M. R., and Tam, V. H. (2012). In vitro activity of MK-7655, a novel β-lactamase inhibitor, in combination with imipenem against carbapenem-resistant Gram-negative bacteria. Antimicrob. Agents Chemother. 56, 3753-3757. doi: 10.1128/AAC.05927-11.
30. Iglicar, P., Legen, I., Vilfan, G., Selic, L., and Prezelj, A. (2009). Permeability of a novel β-lactamase inhibitor LK-157 and its ester prodrugs across rat jejunum in vitro. J. Pharm. Pharmacol. 61, 1211-1218. doi: 10.1211/jpp/61.09.0011.
31. Infectious Diseases Society of America. (2010). The 10 x '20 initiative: pursuing a global commitment to develop 10 new antibacterial drugs by 2020. Clin. Infect. Dis. 50, 1081-1083. doi: 10.1086/652237.
32. Infectious Diseases Society of America. (2012). White paper: recommendations on the conduct of superiority and organism-specific clinical trials of antibacterial agents for the treatment of infections caused by drug-resistant bacterial pathogens. Clin. Infect. Dis. 55, 1031-1046. doi: 10.1093/cid/cis688.
33. King, D. T., Worrall, L. J., Gruninger, R., and Strynadka, N. C. (2012). New Delhi metallo-β-lactamase: structural insights into β-lactam recognition and inhibition. J. Am. Chem. Soc. 134, 11362-11365. doi: 10.1021/ja303579d.
34. Kumarasamy, K. K., Toleman, M. A., Walsh, T. R., Bagaria, J., Butt, F., Balakrishnan, R., 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. doi: 10.1016/S1473-3099(10)70143-2.
35. Lamoureaux, T. L., Vakulenko, V., Toth, M., Frase, H., and Vakulenko, S. B. (2013). A novel extended-spectrum β-lactamase, SGM-1, from an environmental isolate of Sphingobium sp. Antimicrob. Agents Chemother. 57, 3783-3788. doi: 10.1128/AAC.00808-13.
36. Liu, Z., Li, W., Wang, J., Pan, J., Sun, S., Yu, Y., et al. (2013). Identification and characterization of the first Escherichia coli strain carrying NDM-1 gene in China. PLoS ONE 8:e66666. doi: 10.1371/journal.pone.0066666.
37. Livermore, D. M., and Mushtaq, S. (2013). Activity of biapenem (RPX2003) combined with the boronate β-lactamase inhibitor RPX7009 against carbapenem-resistant Enterobacteriaceae. J. Antimicrob. Chemother. 68, 1825-1831. doi: 10.1093/jac/dkt118.
38. Livermore, D. M., Mushtaq, S., and Warner, M. (2009). Activity of the anti-MRSA carbapenem razupenem (PTZ601) against Enterobacteriaceae with defined resistance mechanisms. J. Antimicrob. Chemother. 64, 330-335. doi: 10.1093/jac/dkp187.
39. Livermore, D. M., Mushtaq, S., and Warner, M. (2010). Activity of BAL30376 (monobactam BAL19764 + BAL29880 + clavulanate) versus Gram-negative bacteria with characterized resistance mechanisms. J. Antimicrob. Chemother. 65, 2382-2395. doi: 10.1093/jac/dkq310.
40. Livermore, D. M., Mushtaq, S., Warner, M., Zhang, J., Maharjan, S., Doumith, M., et al. (2011). Activities of NXL104 combinations with ceftazidime and aztreonam against carbapenemase-producing Enterobacteriaceae. Antimicrob. Agents Chemother. 55, 390-394. doi: 10.1128/AAC.00756-10.
41. Livermore, D. M., Warner, M., and Mushtaq, S. (2013). Activity of MK-7655 combined with imipenem against Enterobacteriaceae and Pseudomonas aeruginosa. J. Antimicrob. Chemother. 68, 2286-2290. doi: 10.1093/jac/dkt178.
42. Lucasti, C., Popescu, I., Ramesh, M. K., Lipka, J., and Sable, C. (2013). Comparative study of the efficacy and safety of ceftazidime/avibactam plus metronidazole versus meropenem in the treatment of complicated intra-abdominal infections in hospitalized adults: results of a randomized, double-blind, Phase II trial. J. Antimicrob. Chemother. 68, 1183-1192. doi: 10.1093/jac/dks523.
43. MacGowan, A. P., Noel, A., Tomaselli, S., Elliott, H., and Bowker, K. (2011). Pharmacodynamics of razupenem (PZ601) studied in an in vitro pharmacokinetic model of infection. Antimicrob. Agents Chemother. 55, 1436-1442. doi: 10.1128/AAC.00936-10.
44. Mangion, I. K., Ruck, R. T., Rivera, N., Huffman, M. A., and Shevlin, M. (2011). A concise synthesis of a β-lactamase inhibitor. Org. Lett. 13, 5480-5483. doi: 10.1021/ol202195n.
45. Mushtaq, S., Warner, M., and Livermore, D. M. (2010). In vitro activity of ceftazidime+NXL104 against Pseudomonas aeruginosa and other non-fermenters. J. Antimicrob. Chemother. 65, 2376-2381. doi: 10.1093/jac/dkq306.
46. Mushtaq, S., Woodford, N., Hope, R., Adkin, R., and Livermore, D. M. (2013). Activity of BAL30072 alone or combined with β-lactamase inhibitors or with meropenem against carbapenem-resistant Enterobacteriaceae and non-fermenters. J. Antimicrob. Chemother. 68, 1601-1608. doi: 10.1093/jac/dkt050.
47. Nazik, H., Ongen, B., Ilktac, M., Aydin, S., Kuvat, N., Sahin, A., et al. (2012). Carbapenem resistance due to blaOXA-48 among ESBL-producing Escherichia coli and Klebsiella pneumoniae isolates in a univesity hospital, Turkey. Southeast Asian J. Trop. Med. Public Health 43, 1178-1185.
48. Page, M. G., Dantier, C., and Desarbre, E. (2010). In vitro properties of BAL30072, a novel siderophore sulfactam with activity against multiresistant Gram-negative bacilli. Antimicrob. Agents Chemother. 54, 2291-2302. doi: 10.1128/AAC.01525-09.
49. Page, M. G., Dantier, C., Desarbre, E., Gaucher, B., Gebhardt, K., and Schmitt-Hoffmann, A. (2011). In vitro and in vivo properties of BAL30376, a β-lactam and dual β-lactamase inhibitor combination with enhanced activity against Gram-negative Bacilli that express multiple β-lactamases. Antimicrob. Agents Chemother. 55, 1510-1519. doi: 10.1128/AAC.01370-10.
50. Page, M. G., and Heim, J. (2009). New molecules from old classes: revisiting the development of β-lactams. IDrugs 12, 561-565.
51. Papp-Wallace, K. M., Endimiani, A., Taracila, M. A., and Bonomo, R. A. (2011). Carbapenems: past, present, and future. Antimicrob. Agents Chemother. 55, 4943-4960. doi: 10.1128/AAC.00296-11.
52. Paukner, S., Hesse, L., Prezelj, A., Solmajer, T., and Urleb, U. (2009). In vitro activity of LK-157, a novel tricyclic carbapenem as broad-spectrum β-lactamase inhibitor. Antimicrob. Agents Chemother. 53, 505-511. doi: 10.1128/AAC.00085-08.
53. Plantan, I., Selic, L., Mesar, T., Anderluh, P. S., Oblak, M., Prezelj, A., et al. (2007). 4-Substituted trinems as broad spectrum β-lactamase inhibitors: structure-based design, synthesis, and biological activity. J. Med. Chem. 50, 4113-4121. doi: 10.1021/jm0703237.
54. Pournaras, S., Poulou, A., Voulgari, E., Vrioni, G., Kristo, I., and Tsakris, A. (2010). Detection of the new metallo-β-lactamase VIM-19 along with KPC-2, CMY-2 and CTX-M-15 in Klebsiella pneumoniae. J. Antimicrob. Chemother. 65, 1604-1607. doi: 10.1093/jac/dkq190.
55. Powers, R. A., and Shoichet, B. K. (2002). Structure-based approach for binding site identification on AmpC β-lactamase. J. Med. Chem. 45, 3222-3234. doi: 10.1021/jm020002p.
56. Russo, T. A., Page, M. G., Beanan, J. M., Olson, R., Hujer, A. M., Hujer, K. M., et al. (2011). In vivo and in vitro activity of the siderophore monosulfactam BAL30072 against Acinetobacter baumannii. J. Antimicrob. Chemother. 66, 867-873. doi: 10.1093/jac/dkr013.
57. Sabet, M., Tarazi, Z., Lomovskaya, O., Hecke, S., Dudley, M., and Griffith, O. (2012). "In vivo efficacy of the β-lactamase inhibitor RPX7009 combined with the carbapenem RPX2003 against KPC-producing K. pneumoniae, abstr F-858," in Interscience Conference on Antimicrobial Agents and Chemotherapy (San Francisco, CA).
58. Shlaes, D. M. (2013). New β-lactam-β-lactamase inhibitor combinations in clinical development. Ann. N. Y. Acad. Sci. 1277, 105-114. doi: 10.1111/nyas.12010.
59. Spellberg, B., Bartlett, J. G., and Gilbert, D. N. (2013). The future of antibiotics and resistance. N. Engl. J. Med. 368, 299-302. doi: 10.1056/NEJMp1215093.
60. Tan, Q., Ogawa, A. M., Painter, R. E., Park, Y. W., Young, K., and Dininno, F. P. (2010). 4,7-Dichloro benzothien-2-yl sulfonylaminomethyl boronic acid: first boronic acid-derived β-lactamase inhibitor with class A, C, and D activity. Bioorg. Med. Chem. Lett. 20, 2622-2624. doi: 10.1016/j.bmcl.2010.02.065.
61. Tan, Q., Ogawa, A. M., Raghoobar, S. L., Wisniewski, D., Colwell, L., Park, Y. W., et al. (2011). Thiophenyl oxime-derived phosphonates as nano-molar class C β-lactamase inhibitors reducing MIC of imipenem against Pseudomonas aeruginosa and Acinetobacter baumannii. Bioorg. Med. Chem. Lett. 21, 4363-4365. doi: 10.1016/j.bmcl.2011.04.122.
62. Winkler, M. L., Rodkey, E. A., Taracila, M. A., Drawz, S. M., Bethel, C. R., Papp-Wallace, K. M., et al. (2013). Design and exploration of novel boronic acid inhibitors reveals important interactions with a clavulanic acid-resistant sulfhydryl-variable (SHV) β-lactamase. J. Med. Chem. 56, 1084-1097. doi: 10.1021/jm301490d.
63. Zhanel, G. G., Lawson, C. D., Adam, H., Schweizer, F., Zelenitsky, S., Lagace-Wiens, P. R., et al. (2013). Ceftazidime-avibactam: A novel cephalosporin/β-lactamase inhibitor combination. Drugs 73, 159-177. doi: 10.1007/s40265-013-0013-7.