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Antibiotics: The Need for Innovation
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
The transpeptidase enzyme is classified as a serine protease; where a serine residue in the active site is involved in hydrolysis of peptide bonds. The serine acts as a nucleophile to split the two D-alanine units on a peptide chain. The terminal alanine departs, while the peptide remains in the active site. Another peptide chain enters the active site and a peptide bond is formed between D-alanine and the terminal glycine of the other chain. It is presumed that the penicillin conformation mimics the transition state conformation of the D-Ala-D-Ala moiety during the cross-linking reaction and the transpeptidase enzyme mistakenly binds it to the active site. The serine residue acts as a nucleophile and opens the β-lactam ring, but because the molecule is cyclic, it is not split in two as the peptide would be. Consequently, nothing leaves the active site, which is blocked and access to the second peptide chain is prevented. As a result, cross-linking in the bacterial cell wall is inhibited, making it fragile and lysis occurs.
Basic Microbiology
Published in Philip A. Geis, Cosmetic Microbiology, 2020
The bacteria share several common structural characteristics with eukaryotic cells such as an outer cell membrane and an internal cytosol. In bacteria, together these are referred to as the “protoplast”. However, whereas eukaryotic cells have internal membrane-bound organelles (e.g., the nucleus), bacteria lack these internal organelles and hence the moniker “prokaryotes”, reflecting a common belief that eukaryotic cells evolved from such progenitors. Several observable bacterial cell structures as well as their composition and function(s) are listed in the section that follows (see Figure 1.3). Special attention is given to the bacterial cell wall.
SBA Answers and Explanations
Published in Vivian A. Elwell, Jonathan M. Fishman, Rajat Chowdhury, SBAs for the MRCS Part A, 2018
Vivian A. Elwell, Jonathan M. Fishman, Rajat Chowdhury
Penicillins and cephalosporins (which includes cefuroxime, cefotaxime, ceftriaxone) inhibit bacterial cell wall synthesis through the inhibition of peptidoglycan cross-linking. This weakens the cell wall of bacteria and renders them susceptible to osmotic shock. Macrolides (such as erythromycin), tetracyclines, aminoglycosides, and chloramphenicol act by interfering with bacterial protein synthesis. Sulphonamides (e.g., trimethoprim, co-trimoxazole) work by inhibiting the synthesis of nucleic acid (Table 12).
Discovery of a fragment hit compound targeting D-Ala:D-Ala ligase of bacterial peptidoglycan biosynthesis
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Matic Proj, Martina Hrast, Gregor Bajc, Rok Frlan, Anže Meden, Matej Butala, Stanislav Gobec
Peptidoglycan is a macromolecule essential for bacterial survival and is found only in the bacterial cell wall. Therefore, enzymes involved in the peptidoglycan biosynthetic pathway represent potential targets for the discovery of new antimicrobial agents5,6. Among the intracellular enzymes involved in peptidoglycan biosynthesis, only two enzymes have been validated as antibacterial targets by inhibitors that are in clinical use: UDP-N-acetylglucosamine-enolpyruvyl transferase (MurA, EC 2.5.1.7) is validated by fosfomycin, which is used to treat urinary tract infections7, and D-alanine:D-alanine ligase (Ddl, EC 6.3.2.4) is validated by cycloserine (Figure 1(B)), which is a second-line drug for the treatment of tuberculosis8.
Ceftobiprole medocaril for the treatment of pneumonia
Published in Expert Review of Anti-infective Therapy, 2023
Wan-Hsuan Hsu, Chi-Kuei Hsu, Chih-Cheng Lai
First, ceftobiprole exerts its bactericidal activity by inhibiting transpeptidases, showing strong affinities to PBP 2a, PBP2×, and PBP3. PBP2a, PBP2×, and PBP3 are responsible for β-lactam drug resistance in MRSA, PRSP, and MSSA respectively [31]. In addition, it can interfere with peptidoglycan biosynthesis of the bacterial cell wall in order to kill antibiotic-resistant bacteria. Second, the plasma protein binding of ceftobiprole is minimal, and it can achieve high concentrations in excess of the MICs for the causative pathogens in the ELFs [25,26]. And third, ceftobiprole exhibits potent in vitro activity against a wide range of susceptible pathogens, including S. aureus, S. pneumoniae, Viridans streptococci, H. influenzae, M. catarrhalis, and Enterobacterales. Besides, both CA-MRSA and HA-MRSA were susceptible to ceftobiprole with an overall susceptibility rate of more than 99.2% [35,37,39,42]. P. aeruginosa, an important HAP-causing pathogen, has shown to be susceptible to ceftobiprole with a rate ranging from 62.4% to 86.0% [36–38,42]. Lastly, the clinical efficacy and safety of ceftobiprole in the treatment of pediatric and adult patients with CAP and HAP excluding VAP have been demonstrated by several RCTs (NCT00326287, NCT00210964, NCT00229008, NCT03439124) [47–49]. Further subgroup analysis and our meta-analysis demonstrated consistent findings.
In vitro strain specific reducing of aflatoxin B1 by probiotic bacteria: a systematic review and meta-analysis
Published in Toxin Reviews, 2022
Alireza Emadi, Majid Eslami, Bahman Yousefi, Anna Abdolshahi
The Incubation temperature can be strongly influenced by the aflatoxin detoxification proficiency of probiotic bacteria. El-Nezami et al. proposed that 37 °C was the best temperature for binding of aflatoxin B1 by Lactobacillus rhamnosus GG and Lactobacillus rhamnosus LC-705 (El-Nezami et al.1998a). Rahaie et al. shown that the surface attachment efficiency of Lactobacillus to aflatoxins could improve by heat treatment (Rahaie et al.2012). However, thermal treatment of probiotic bacteria seems to increase their binding level to aflatoxins. Not only is the bacterial cell wall available in this way, but other wall components can also contribute to this process. Although, the binding to aflatoxins may be reversible in untreated cells (Kuharić et al.2018). Lee et al. identified that temperature dealing could cause a decline in the hydrophobicity and enhance the adsorption affinity. Thus hydrophobic interactions take part in the adsorption of aflatoxin B1 (Lee et al.2003).