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Clinical Pharmacology of the Anti-Tuberculosis Drugs
Published in Lloyd N. Friedman, Martin Dedicoat, Peter D. O. Davies, Clinical Tuberculosis, 2020
Gerry Davies, Charles Peloquin
Imipenem (IMP) and meropenem (MRP) are highly water-soluble weak acids (log P −3.9 and −4.4, pKa 3.2 and 3.47–9.39, MW 299.3 and 383.15). Both are synthetic derivatives of thienamycin, a natural product of Streptomyces cattleya. Carbapenems target multiple transpeptidases (penicillin-binding proteins) involved in bacterial cell-wall synthesis including the unique l,d-transpeptidases characteristic of mycobacteria.270 However, M. tuberculosis possesses an extended spectrum class A β-lactamase (BlaC), which must be inactivated for in vitro activity of the drugs.271 Clavulanic acid is the most potent inhibitor of BlaC among licensed β-lactamase inhibitors.272 MIC99s of meropenem–clavulanate in wild-type MDR and XDR strains range from 0.125 to 2 μg/mL.273
Halogenases with Potential Applications for the Synthesis of Halogenated Pharmaceuticals
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Georgette Rebollar-Pérez, Cynthia Romero-Guido, Antonino Baez, Eduardo Torres
Due to the tight solvation of fluoride anions in water, and the consequently reduction on their nucleophilicity, fluorination reactions are less common. Much of the mechanistic and functional understanding of fluorinases came from the knowledge about fluorinase from Streptomyces cattleya. This enzyme catalyzes the fluorination of S-adenosyl methionine to produce 5-deoxy-5-fluoroadenosine in a SN2-type reaction (Fig. 16.1e). Crystallography studies shown that fluoride ion is placed in a SN2-like trajectory to the ribose 5-C,348, consistent with the observation that introduction of fluoride occurs with inversion of stereochemistry as reported (Dong et al., 2004; Zhu et al., 2007).
Imipenem–Cilastatin and Imipenem–Relebactam
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Yoshiro Hayashi, David L. Paterson
In the 1970s Beecham Research Laboratories identified a carbapenem group called olivanic acids, which were beta-lactamase inhibitors and broad spectrum antibiotics (Butterworth et al., 1979). At about the same time, Merck, Sharp and Dohme Research Laboratories independently identified thienamycin, derived from Streptomyces cattleya. This had the same carbapenem nucleus but different side chains, which increased its antibacterial potency (Cassidy et al., 1981). Its chemical instability in concentrated solution was overcome by crystallization of the N-formimidoyl derivative of thienamycin, called imipenem. Urinary recovery In vivo was less than expected due to extensive renal tubular metabolism by a brush border dipeptidase enzyme, dehydropeptidase I. A selective competitive antagonist of this enzyme was then developed and named cilastatin, which has similar pharmacokinetics to imipenem. Imipenem and cilastatin are marketed in combination in a 1:1 ratio (Kahan et al.,1983). Cilastatin not only prevents the degradation of imipenem but may also protect the kidneys against potential toxic effects exerted by higher doses of imipenem (Rodloff et al., 2006). The chemical structure of imipenem is shown in Figure 37.1.
Selected strategies to fight pathogenic bacteria
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Aiva Plotniece, Arkadij Sobolev, Claudiu T. Supuran, Fabrizio Carta, Fredrik Björkling, Henrik Franzyk, Jari Yli-Kauhaluoma, Koen Augustyns, Paul Cos, Linda De Vooght, Matthias Govaerts, Juliana Aizawa, Päivi Tammela, Raivis Žalubovskis
Doripenem is a new thienamycin-inspired antibiotic, which can be used parenterally. Thienamycin, isolated from Streptomyces cattleya in 1976, was found highly activity against both Gram-positive and Gram-negative bacteria and is resistant to bacterial β-lactamase, however, this compound was too metabolically unstable to be further developed9. The thienamycin analogue doripenem has an enhanced metabolic stability to renal dehydropeptidase-1 due to the 1β-methyl substituent in the carbapenem skeleton10. Doripenem is a broad-spectrum antibiotic against many pathogenic bacteria, including the Gram-negative Pseudomonas aeruginosa. The key synthetic step (Scheme 3) is a coupling between the 4-nitrobenzyl-protected enol phosphate and substituted 3-mercaptopyrrolidine11.
An overview of cilastatin + imipenem + relebactam as a therapeutic option for hospital-acquired and ventilator-associated bacterial pneumonia: evidence to date
Published in Expert Opinion on Pharmacotherapy, 2021
Júlia Sellarès-Nadal, Simeón Eremiev, Joaquin Burgos, Benito Almirante
Imipenem (N-formimidoyl-thienamycin) is a broad-spectrum antimicrobial agent that belongs to the carbapenem family. Carbapenems are β-lactams that are derived from thienamycin, which is produced by Streptomyces cattleya, a soil organism [28]. Their difference from penicillins is the substitution of a carbon atom rather than the sulfur atom at C1 and the presence of a double bond between C2 and C3 in the five-membered ring structure [29]. The carbon atom at C1 improves the efficacy and spectrum of carbapenems. Moreover, carbapenems are intrinsically resistant to hydrolysis by a great number of β-lactamases due to their hydroxyethyl side chain at C6 [30]. The trans configuration at C6 is characteristic of carbapenems, in contrast to the cis side chains of penicillins and cephalosporins, and explains the stability of carbapenems to β-lactamases. In the renal tubules, imipenem undergoes rapid degradation by an enzyme called dehydropeptidase (DPH-1). This is the reason why cilastatin must be administered, a molecule that has no antimicrobial activity but plays a role in inhibiting DPH-1, decreasing the nephrotoxic metabolites of impipenem. Other mechanism why cilastin prevent nephrotoxicity of imipenem are by the anti-inflammatory and antioxidative activity, as well as the reduction of renal transport and accumulation of toxins [23,25]
Evaluating imipenem + cilastatin + relebactam for the treatment of complicated urinary tract infections
Published in Expert Opinion on Pharmacotherapy, 2020
S.G. Kuiper, E. Leegwater, E.B. Wilms, C. van Nieuwkoop
Imipenem is, like all carbapenems, a derivate of thienamycin. Thienamycin is produced by Streptomyces cattleya, as well as penicillin. Carbapenems contain a β-lactam structure but differ to penicillin by having a double-bond link between carbon atoms in positions 2 and 3 and having a carbon atom instead of sulfur in position 1. Imipenem is the N-formimidoyl derivate of thienamycin and in contrast to thienamycin, has a formamidine sidechain at carbon 2 instead of cysteamine [6,7]. This improves the chemical stability of imipenem. Imipenem is a substrate for renal dehydropeptidase-1 (DHP-1). Therefore, it is needed to add cilastatin (a DHP-1 inhibitor) to increase the urinary concentration and renal recovery rate [8].