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Medicines in neonates
Published in Evelyne Jacqz-Aigrain, Imti Choonara, Paediatric Clinical Pharmacology, 2021
Evelyne Jacqz-Aigrain, Imti Choonara
Both antibiotics target bacterial membrane synthesis and are inhibitors of the peptidoglycan synthesis, although their modes of action are distinctive. Both the killing effect of 13-lactams and minimising bacterial resistance are maximal, while their concentration at the site of infection is continuously above the MIC. A concentration four times greater than the MIC is recommended (Table 1). 13-lactams, except carbapenems, show no PAE for gram negative bacilli. Glycopep-tides have a longer bacteriostasis for gram positive bacteria than β-lactams.
Basic Microbiology
Published in Philip A. Geis, Cosmetic Microbiology, 2020
Free-living bacteria require protection against osmotic stresses. Osmotic stress is encountered when bacteria enter hypotonic or hypertonic environments depending on the concentration of solutes within the cell. This can lead water to cross the plasma membrane by osmosis in an attempt to normalize solute concentrations across the membrane. Excess gain of water can cause the bacteria to lyse or explode due to cellular swelling whereas excess loss of water can cause membrane rupture by excessive shrinkage (plasmolysis). Most bacteria utilize a carbohydrate-based cell wall in order to provide resistance to osmotic forces. The basis of the cell wall is a macromolecular complex unique to bacteria called “peptidoglycan” or murein (Figure 1.4). The basic repeating structure of peptidoglycan is a disaccharide comprising N-acetylglucosamine (NAG) linked to N-acetylmuramic acid (NAM). This disaccharide is repeated hundreds of times to build long carbohydrate chains that are linked together by short peptides (called stem peptides) that contain unusual amino acids, some not found in proteins. These long chains appear to be wound into helices first and then cross-linked to other helices to form the peptidoglycan structure (2). The peptidoglycan is attached firmly to the cell membrane by lipoproteins. Although bacteria have proteins that determine the overall morphology of the cell, the peptidoglycan reinforces that morphology.
Urinary Tract Infections (UTI)
Published in Manit Arya, Taimur T. Shah, Jas S. Kalsi, Herman S. Fernando, Iqbal S. Shergill, Asif Muneer, Hashim U. Ahmed, MCQs for the FRCS(Urol) and Postgraduate Urology Examinations, 2020
Nish Bedi, Ali Omar, Jas S. Kalsi
Quinolones rapidly inhibit DNA synthesis by promoting cleavage of bacterial DNA in the DNA-enzyme complexes of DNA gyrase and type IV topoisomerase, resulting in rapid bacterial death [4]. Penicillin kills susceptible bacteria by specifically inhibiting the transpeptidase that catalyses the final step in cell wall biosynthesis, the cross-linking of peptidoglycan [5]. Macrolides bind to 50S subunit of ribosomes (does not exist in human cells). More specifically to the peptidyl transferase site. The aminoglycosides primarily act by binding to the aminoacyl site of 16S ribosomal RNA within the 30S ribosomal subunit, leading to misreading of the genetic code and inhibition of translocation [6,7].
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.
Impact of chronic medications in the perioperative period: mechanisms of action and adverse drug effects (Part I)
Published in Postgraduate Medicine, 2021
Ofelia Loani Elvir-Lazo, Paul F White, Hillenn Cruz Eng, Firuz Yumul, Raissa Chua, Roya Yumul
Aminoglycosides inhibit bacterial protein synthesis by binding to the 16S rRNA component of the 30S ribosome subunit [56]. Beta-lactams (e.g. penicillins, cephalosporins, and carbapenems) and glycopeptides (e.g. vancomycin) interfere with specific steps in bacterial cell wall biosynthesis, resulting in cell lysis. Beta-lactams block the cross-linking of peptidoglycan units by inhibiting the peptide bond formation reaction catalyzed by penicillin-binding proteins (PBP). Vancomycin achieves the same inhibition by blocking the transglucosylase and PBP activity [56]. Fluoroquinolones inhibit DNA synthesis by targeting the enzyme DNA gyrase, which is a topoisomerase, which prevents bacteria from replicating its DNA. Cyclic lipopeptides (daptomycin) also inhibit cell wall synthesis by altering the structural integrity of bacteria by inserting themselves into the cell membrane and inducing membrane depolarization [57]. Nitroimidazoles (metronidazole) inhibits protein synthesis by forming cytotoxic nitro-radical anions that result in DNA strand breakage [58].
The interplay between gut bacteria and the yeast Candida albicans
Published in Gut Microbes, 2021
Some of the most recognizable bacterial components are those found in their outer membrane and cell wall. Molecules derived from these structures are also among the most abundant microbial products in the gut.44 Peptidoglycan, for example, is a major component of the bacterial cell wall. It consists of alternating β-(1,4)-linked N-acetylglucosamine and N-acetylmuramic acid cross-linked by regularly spaced short peptides. Certain bacterial peptidoglycan subunits such as 1,6-anhydro-N-acetylmuramyl peptides are strong hypha-inducing agents in C. albicans.45 This is consistent with the observation that the amino sugar N-acetylglucosamine also promotes hyphal morphogenesis.46,47 In a recent study in mice,48 it was shown that β-lactam antibiotic treatment promoted C. albicans hyphal growth in the gastrointestinal tract due to the release of bacterial peptidoglycan subunits in the intestinal lumen (Figure 1a). Furthermore, the authors established that the filamenting C. albicans cells under these conditions could disseminate from the gut causing invasive candidiasis. The β-lactam mediated effect on the fungus could explain, at least in part, the general observation that antibiotic treatment constitutes a major risk factor for Candida dissemination from the gut.