Generic placeholder image

Current Drug Research Reviews

Editor-in-Chief

ISSN (Print): 2589-9775
ISSN (Online): 2589-9783

Review Article

Carbapenem Antibiotics: Recent Update on Synthesis and Pharmacological Activities

Author(s): Abhishek Tiwari*, Varsha Tiwari, Biswa Mohan Sahoo, Bimal Krishna Banik, Manish Kumar and Navneet Verma

Volume 15, Issue 1, 2023

Published on: 07 November, 2022

Page: [35 - 61] Pages: 27

DOI: 10.2174/2589977514666220907141939

Price: $65

Abstract

Right from the breakthrough of carbapenems since 1976, many schemes on synthesis, structure-activity relationship (SAR), and biological activities have been carried out, and several carbapenems have been developed, including parentally active carbapenems like imipenem, doripenem, biapenem, meropenem, ertapenem, panipenem, razupenem, tomopenem, and cilastatin, whereas orally active carbapenems like GV-118819, GV-104326, CS-834, L-084, DZ-2640, CL 191, 121, L-646, 591, S-4661, ER-35768, MK-826. Prodrugs of carbapenem with increased bioavailability include temopenem, tebipenem, sanfetrinem, LK-157, and CP 5484. Merck, Glaxo Welcome Research Group, Johnson & Johnson, Sankyo Group and Dai-ichi Group, and Wyeth-Ayerst Group were among the businesses that produced carbapenems. In this review Witting reaction, Mitsunobu reaction, Dieckmann reaction, palladium-catalyzed hydrogenolysis, E. coli-based cloned synthesis, as well as biosynthetic enzymes such as carbapenem synthetase (carA), carboxymethylproline synthase (carB), carbapenem synthase (carC) are included. Carbapenems are biologically mainly active in the infections like urinary tract infections, bloodstream infections, tuberculosis, intra-abdominal infections, and pathogens like anaerobes, gram-positive and gram-negative bacteria.

Keywords: Carbapenem, antibiotics, structure, chemistry, resistance, mechanism of action.

Graphical Abstract
[1]
Bush K, Bradford PA. β-Lactams and β-Lactamase inhibitors: An overview. Cold Spring Harb Perspect Med 2016; 6(8): a025247.
[http://dx.doi.org/10.1101/cshperspect.a025247] [PMID: 27329032]
[2]
Breilh D, Texier-Maugein J, Allaouchiche B, Saux MC, Boselli E. Carbapenems. J Chemother 2013; 25(1): 1-17.
[http://dx.doi.org/10.1179/1973947812Y.0000000032] [PMID: 23433439]
[3]
Nicolau DP. Carbapenems: A potent class of antibiotics. Expert Opin Pharmacother 2008; 9(1): 23-37.
[http://dx.doi.org/10.1517/14656566.9.1.23] [PMID: 18076336]
[4]
Hellinger WC, Brewer NS. Carbapenems and monobactams: Imipenem, meropenem, and aztreonam. Mayo Clin Proc 1999; 74(4): 420-34.
[http://dx.doi.org/10.4065/74.4.420] [PMID: 10221472]
[5]
El-Gamal MI, Brahim I, Hisham N, Aladdin R, Mohammed H, Bahaaeldin A. Recent updates of carbapenem antibiotics. Eur J Med Chem 2017; 131: 185-95.
[http://dx.doi.org/10.1016/j.ejmech.2017.03.022] [PMID: 28324783]
[6]
Akama H, Matsuura T, Kashiwagi S, et al. Crystal structure of the membrane fusion protein, MexA, of the multidrug transporter in Pseudomonas aeruginosa. J Biol Chem 2004; 279(25): 25939-42.
[http://dx.doi.org/10.1074/jbc.C400164200] [PMID: 15117957]
[7]
Kumagai T, Tamai S, Abe T, Hikda M. Current status of oral carbapenem development. Curr Med Anti Infect Agents 2002; 1(1): 1-14.
[http://dx.doi.org/10.2174/1568012023355018]
[8]
Nguyen M, Joshi SG. Carbapenem resistance in Acinetobacter baumannii, and their importance in hospital‐acquired infections: A scientific review. J Appl Microbiol 2021; 131(6): 2715-38.
[http://dx.doi.org/10.1111/jam.15130] [PMID: 33971055]
[9]
Vrancianu CO, Dobre EG, Gheorghe I, Barbu I, Cristian RE, Chifiriuc MC. Present and future perspectives on therapeutic options for carbapenemase-producing Enterobacterales Infections. Microorganisms 2021; 9(4): 730.
[http://dx.doi.org/10.3390/microorganisms9040730] [PMID: 33807464]
[10]
Pastel DA. Imipenem-cilastatin sodium, a broad-spectrum carbapenem antibiotic combination. Am J Health Syst Pharm 1986; 43(10): 2630-44.
[http://dx.doi.org/10.1093/ajhp/43.10.2630] [PMID: 3530614]
[11]
Livermore DM, Sefton AM, Scott GM. Properties and potential of ertapenem. J Antimicrob Chemother 2003; 52(3): 331-44.
[http://dx.doi.org/10.1093/jac/dkg375] [PMID: 12917243]
[12]
Shah PM, Isaacs RD. Ertapenem, the first of a new group of carbapenems. J Antimicrob Chemother 2003; 52(4): 538-42.
[http://dx.doi.org/10.1093/jac/dkg404] [PMID: 12951340]
[13]
Golan Y. Empiric therapy for hospital-acquired, gram-negative complicated intra-abdominal infection and complicated urinary tract infections: A systematic literature review of current and emerging treatment options. BMC Infect Dis 2015; 15(1): 313.
[http://dx.doi.org/10.1186/s12879-015-1054-1] [PMID: 26243291]
[14]
Matsumoto T, Muratani T. Newer carbapenems for urinary tract infections. Int J Antimicrob Agents 2004; 24(1) (Suppl. 1): 35-8.
[http://dx.doi.org/10.1016/j.ijantimicag.2004.03.001] [PMID: 15364304]
[15]
American thoracic society; Infectious diseases society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med 2005; 171(4): 388-416.
[http://dx.doi.org/10.1164/rccm.200405-644ST] [PMID: 15699079]
[16]
Woodhead M, Blasi F, Ewig S, et al. Guidelines for the management of adult lower respiratory tract infections - Full version. Clin Microbiol Infect 2011; 17(6) (Suppl. 6): E1-E59.
[http://dx.doi.org/10.1111/j.1469-0691.2011.03672.x] [PMID: 21951385]
[17]
Amit S, Mishali H, Kotlovsky T, Schwaber MJ, Carmeli Y. Bloodstream infections among carriers of carbapenem-resistant Klebsiella pneumoniae: Etiology, incidence and predictors. Clin Microbiol Infect 2015; 21(1): 30-4.
[http://dx.doi.org/10.1016/j.cmi.2014.08.001] [PMID: 25636924]
[18]
Ramón-García S, et al. Sanfetrinem, repurposing an oral beta-lactam with intracellular activity for the treatment of tuberculosis. Abstract book of the 50th world conference on lung health of the international union against tuberculosis and lung disease (The Union). Int J Tuberc Lung Dis 2019; 23(10): S591.
[19]
Shomar H, Gontier S, van den Broek NJF, et al. Metabolic engineering of a carbapenem antibiotic synthesis pathway in Escherichia coli. Nat Chem Biol 2018; 14(8): 794-800.
[http://dx.doi.org/10.1038/s41589-018-0084-6] [PMID: 29942079]
[20]
Sleeman MC, Sorensen JL, Batchelar ET, McDonough MA, Schofield CJ. Structural and mechanistic studies on carboxymethylproline synthase (CarB), a unique member of the crotonase superfamily catalyzing the first step in carbapenem biosynthesis. J Biol Chem 2005; 280(41): 34956-65.
[http://dx.doi.org/10.1074/jbc.M507196200] [PMID: 16096274]
[21]
Coulthurst SJ, Barnard AML, Salmond GPC. Regulation and biosynthesis of carbapenem antibiotics in bacteria. Nat Rev Microbiol 2005; 3(4): 295-306.
[http://dx.doi.org/10.1038/nrmicro1128] [PMID: 15759042]
[22]
Wright PM, Seiple IB, Myers AG. The evolving role of chemical synthesis in antibacterial drug discovery. Angew Chem Int Ed 2014; 53(34): 8840-69.
[http://dx.doi.org/10.1002/anie.201310843] [PMID: 24990531]
[23]
Rodríguez M, Núñez LE, Braña AF, Méndez C, Salas JA, Blanco G. Mutational analysis of the thienamycin biosynthetic gene cluster from Streptomyces cattleya. Antimicrob Agents Chemother 2011; 55(4): 1638-49.
[http://dx.doi.org/10.1128/AAC.01366-10] [PMID: 21263049]
[24]
Salzmann TN, Ratcliffe RW, Christensen BG, Bouffard FA. A stereocontrolled synthesis of (+)-thienamycin. J Am Chem Soc 1980; 102(19): 6161-3.
[http://dx.doi.org/10.1021/ja00539a040]
[25]
Chang W, Guo Y, Wang C, et al. Mechanism of the C5 stereoinversion reaction in the biosynthesis of carbapenem antibiotics. Science 2014; 343(6175): 1140-4.
[http://dx.doi.org/10.1126/science.1248000] [PMID: 24604200]
[26]
Kershaw NJ, Caines MEC, Sleeman MC, Schofield CJ. The enzymology of clavam and carbapenem biosynthesis. Chem Commun 2005; 34(34): 4251-63.
[http://dx.doi.org/10.1039/b505964j] [PMID: 16113715]
[27]
Arnould JC, Landier F, Pasquet MJ. New applications of the mitsunobu reaction in the synthesis of C-2 N-methyl carbapenems. Tetrahedron Lett 1992; 33(47): 7133-6.
[http://dx.doi.org/10.1016/S0040-4039(00)60855-9]
[28]
Banik BK, Manhas MS, Newaz SN, Bose AK. Facile preparation of carbapenem synthons via microwave-induced rapid reaction. Bioorg Med Chem Lett 1993; 3(11): 2363-8.
[http://dx.doi.org/10.1016/S0960-894X(01)80956-2]
[29]
Banik BK. Heterocyclic Scaffolds I.In: Topics in Heterocyclic Chemistry. Berlin, Heidelberg: Springer 2010; pp. 1-379.
[http://dx.doi.org/10.1007/978-3-642-12845-5]
[30]
Banik BK. β-Lactams: Synthesis and Biological Evaluation. In: Topics in Heterocyclic Chemistry. Berlin, Heidelberg, Springer, 2012; 30: 1-226.
[31]
Banik I, Banik BK. Microwave-induced chemical manipulation of β- lactam. Springer 2012; 88: pp. 781-1007.
[32]
Banik BK. Beta Lactams: Novel Synthetic Pathways and Applications. Springer 2017; pp. 1-419.
[http://dx.doi.org/10.1007/978-3-319-55621-5]
[33]
Parvatkar PT, Parameswaran PS, Banik BK. Solid phase synthesis of β-Lactams: Results and scope. In: Beta lactams: Novel synthetic pathways and applications. Kyoto: Spinger 2017; pp. 253-84.
[34]
Basu S, Banik BK. Beta Lactams as Clinically Active Molecules in Beta Lactams: Novel Synthetic Pathways and Applications. Springer 2017; pp. 285-310.
[35]
Banik BK. Synthesis and Biological Studies of Novel β-Lactams. CRC Book 2013; pp. 31-72.
[http://dx.doi.org/10.1201/b13867-4]
[36]
Dubée V, Arthur M, Fief H, et al. Kinetic analysis of Enterococcus faecium L,D-transpeptidase inactivation by carbapenems. Antimicrob Agents Chemother 2012; 56(6): 3409-12.
[http://dx.doi.org/10.1128/AAC.06398-11] [PMID: 22450984]
[37]
Marous DR, Lloyd EP, Buller AR, et al. Consecutive radical S -adenosylmethionine methylations form the ethyl side chain in thienamycin biosynthesis. Proc Natl Acad Sci USA 2015; 112(33): 10354-8.
[http://dx.doi.org/10.1073/pnas.1508615112] [PMID: 26240322]
[38]
Miyadera T, Sugimura Y, Hashimoto T, et al. Synthesis and in vitro activity of a new carbapenem, RS-533. J Antibiot 1983; 36(8): 1034-9.
[http://dx.doi.org/10.7164/antibiotics.36.1034] [PMID: 6630055]
[39]
Tanabe Y, Manta N, Nagase R, et al. Practical short synthesis of 1β-methylcarbapenem utilizing a new dehydration type ti-dieckmann condensation. Adv Synth Catal 2003; 345(8): 967-70.
[http://dx.doi.org/10.1002/adsc.200303065]
[40]
Mori M, Oida S. A short-step synthesis of orally active carbapenem antibiotic CS-834. Chem Pharm Bull 2000; 48(1): 126-30.
[http://dx.doi.org/10.1248/cpb.48.126] [PMID: 10705488]
[41]
Hakimelahi GH, Moosavi-Movahedi AA, Saboury AA, Osetrov V, Khodarahmi GA, Shia KS. Carbapenem-based prodrugs. Design, synthesis, and biological evaluation of carbapenems. Eur J Med Chem 2005; 40(4): 339-49.
[http://dx.doi.org/10.1016/j.ejmech.2004.11.002] [PMID: 15804533]
[42]
Stapon A, Li R, Townsend CA. Synthesis of (3S,5R)-carbapenam-3-carboxylic acid and its role in carbapenem biosynthesis and the stereoinversion problem. J Am Chem Soc 2003; 125(51): 15746-7.
[http://dx.doi.org/10.1021/ja037665w] [PMID: 14677956]
[43]
Galeazzi R, Geremia S, Mobbili G, Orena M. Diastereoselective synthesis of 3,4-trans-disubstituted pyrrolidin-2-ones via conjugate addition. Tetrahedron Asymmetry 1996; 7: 79.
[http://dx.doi.org/10.1016/0957-4166(95)00423-8]
[44]
Singh SB, Rindgen D, Bradley P, et al. Design, synthesis, and evaluation of prodrugs of ertapenem. ACS Med Chem Lett 2013; 4(8): 715-9.
[http://dx.doi.org/10.1021/ml400092n] [PMID: 24900737]
[45]
Iavarone L, Bottacini M, Pugnaghi F, Morandini C, Grossi P. Sanfetrinem and sanfetrinem-cilexetil: Disposition in rat and dog. Xenobiotica 1997; 27(7): 693-709.
[http://dx.doi.org/10.1080/004982597240280] [PMID: 9253146]
[46]
Paukner S, Hesse L, Preželj A, Šolmajer T, Urleb U. In vitro activity of LK-157, a novel tricyclic carbapenem as broad-spectrum beta-lactamase inhibitor. Antimicrob Agents Chemother 2009; 53(2): 505-11.
[http://dx.doi.org/10.1128/AAC.00085-08] [PMID: 19075067]
[47]
Maruyama T, Yamamoto Y, Kano Y, et al. CP5484, a novel quaternary carbapenem with potent anti-MRSA activity and reduced toxicity. Bioorg Med Chem 2007; 15(19): 6379-87.
[http://dx.doi.org/10.1016/j.bmc.2007.06.057] [PMID: 17681767]
[48]
Papp-Wallace KM, Endimiani A, Taracila MA, Bonomo RA. Carbapenems: Past, present, and future. Antimicrob Agents Chemother 2011; 55(11): 4943-60.
[http://dx.doi.org/10.1128/AAC.00296-11] [PMID: 21859938]
[49]
Burton G, Clear NJC, Eglington AJ, et al. Novel C-2 substituted carbapenem derivatives. Part I. Synthesis and biological activity of non-aromatic heterocyclic derivatives. J Antibiot 1996; 49(12): 1258-65.
[http://dx.doi.org/10.7164/antibiotics.49.1258] [PMID: 9031672]
[50]
Masschelein J, Jenner M, Challis GL. Antibiotics from Gram-negative bacteria: A comprehensive overview and selected biosynthetic highlights. Nat Prod Rep 2017; 34(7): 712-83.
[http://dx.doi.org/10.1039/C7NP00010C] [PMID: 28650032]
[51]
Baughman RP. The use of carbapenems in the treatment of serious infections. J Intensive Care Med 2009; 24(4): 230-41.
[http://dx.doi.org/10.1177/0885066609335660] [PMID: 19617229]
[52]
England K, Boshoff HIM, Arora K, et al. Meropenem-clavulanic acid shows activity against Mycobacterium tuberculosis in vivo. Antimicrob Agents Chemother 2012; 56(6): 3384-7.
[http://dx.doi.org/10.1128/AAC.05690-11] [PMID: 22450968]
[53]
Kumar P, Singh UB, Lamichhane G, Story-Roller E. Repurposing of Carbapenems for the treatment of drug-resistant tuberculosis. In: Hasnain S, Ehtesham N, Grover S, Eds. Mycobacterium tuberculosis: Molecular infection biology, pathogenesis, diagnostics and new interventions. Singapore: Springer 2019; pp 355-74.
[http://dx.doi.org/10.1007/978-981-32-9413-4_26]
[54]
Sotgiu G, D’Ambrosio L, Centis R, et al. Carbapenems to treat multidrug and extensively drug-resistant tuberculosis: A systematic review. Int J Mol Sci 2016; 17(3): 373.
[http://dx.doi.org/10.3390/ijms17030373] [PMID: 26985890]
[55]
ten Doesschate T, van der Vaart TW, Damen JAA, Bonten MJM, van Werkhoven CH. Carbapenem-alternative strategies for complicated urinary tract infections: A systematic review of randomized controlled trials. J Infect 2020; 81(4): 499-509.
[http://dx.doi.org/10.1016/j.jinf.2020.08.008] [PMID: 32795483]
[56]
Li X, Ye H. Clinical and mortality risk factors in bloodstream infections with carbapenem-resistant enterobacteriaceae. Can J Infect Dis Med Microbiol 2017; 2017: 1-5.
[http://dx.doi.org/10.1155/2017/6212910]
[57]
Romanelli G, Cravarezza P, Pozzi A, et al. Carbapenems in the treatment of severe community-acquired pneumonia in hospitalized elderly patients: A comparative study against standard therapy. J Chemother 2002; 14(6): 609-17.
[http://dx.doi.org/10.1179/joc.2002.14.6.609] [PMID: 12583553]
[58]
Fernández-Canigia L, Litterio M, Legaria MC, et al. First national survey of antibiotic susceptibility of the Bacteroides fragilis group: Emerging resistance to carbapenems in Argentina. Antimicrob Agents Chemother 2012; 56(3): 1309-14.
[http://dx.doi.org/10.1128/AAC.05622-11] [PMID: 22232282]
[59]
Fung-Tomc JC, Huczko E, Banville J, et al. Structure-activity relationships of carbapenems that determine their dependence on porin protein D2 for activity against Pseudomonas aeruginosa. Antimicrob Agents Chemother 1995; 39(2): 394-9.
[http://dx.doi.org/10.1128/AAC.39.2.394] [PMID: 7726504]
[60]
Codjoe F, Donkor E. Carbapenem resistance: A review. Med Sci 2017; 6(1): 1.
[http://dx.doi.org/10.3390/medsci6010001] [PMID: 29267233]
[61]
Jeon J, Lee J, Lee J, et al. Structural basis for carbapenem-hydrolyzing mechanisms of carbapenemases conferring antibiotic resistance. Int J Mol Sci 2015; 16(12): 9654-92.
[http://dx.doi.org/10.3390/ijms16059654] [PMID: 25938965]
[62]
Poirel L, Naas T, Nordmann P. Diversity, epidemiology, and genetics of class D beta-lactamases. Antimicrob Agents Chemother 2010; 54(1): 24-38.
[http://dx.doi.org/10.1128/AAC.01512-08] [PMID: 19721065]
[63]
Naas T, Dortet L, Iorga BI. Structural and functional aspects of class A carbapenemases. Curr Drug Targets 2016; 17(9): 1006-28.
[http://dx.doi.org/10.2174/1389450117666160310144501] [PMID: 26960341]
[64]
Evans BA, Amyes SGB. OXA β-Lactamases. Clin Microbiol Rev 2014; 27(2): 241-63.
[http://dx.doi.org/10.1128/CMR.00117-13] [PMID: 24696435]
[65]
Vázquez-Ucha JC, Arca-Suárez J, Bou G, Beceiro A. New carbapenemase inhibitors: Clearing the way for the β-lactams. Int J Mol Sci 2020; 21(23): 9308.
[http://dx.doi.org/10.3390/ijms21239308] [PMID: 33291334]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy