Introduction to Clinical Microbiology
Keith Struthers in Clinical Microbiology, 2017
The peptidoglycan polymer is cross-linked by short peptide side chains that are essential for the stability of the peptidoglycan and cell wall. Cross-linking is carried out by trans- and carboxy-peptidases, enzymes anchored in the cytoplasmic membrane; these are also known as the penicillin-binding proteins (PBP) (Figure 1.7). Note that while the number of different PBP may be five or more, three are used for illustrative purposes in this book. The amino acid serine is the key component in the active site of these enzymes. It is also the target of the β-lactam antibiotics (penicillins, cephalosporins and carbapenems) whose activity resides in the β-lactam ring (Figure 1.8). Covalent binding of a β-lactam antibiotic to the serine residue of the PBP inactivates the enzyme, preventing cross-linking (Figures 1.9a,b). Without the protective peptidoglycan mesh, the unprotected cytoplasmic membrane and cell contents bulge through defects in the mesh and the cell bursts.
Streptococcus pneumoniae
Peter M. Lydyard, Michael F. Cole, John Holton, William L. Irving, Nino Porakishvili, Pradhib Venkatesan, Katherine N. Ward in Case Studies in Infectious Disease, 2010
S. pneumoniae, once highly susceptible to penicillin, has now acquired resistance to this and many other antibiotics. Penicillin resistance results from the generation of penicillin-binding proteins (PBPs) with decreased affinity for penicillin. PBPs are involved in the assembly of the cell wall. It is likely that these altered PBP genes arose by interspecies recombination in which segments of the PBPs’ structural genes were replaced by regions derived from PBP genes of oral streptococci. These altered PBP genes of penicillin-resistant pneumococci can be spread horizontally to sensitive pneumococci by transformation. About one-third of the strains isolated in the United States are resistant to penicillin and higher rates of resistance have been observed in other countries. Although there are over 90 S. pneumoniae serotypes, over 90% of penicillin-resistant strains are found within seven serotypes (6A, 6B, 9V, 14, 19A, 19F, and 23F). Unfortunately, these are the same serotypes that cause the vast majority of infections in children. Cefotaxime, ceftriaxone, and clindamycin are effective antibiotics for treating pneumonia caused by penicillin-resistant pneumococcal isolates that are susceptible to these antibiotics. Clindamycin or vancomycin is recommended when a pneumococcal isolate is resistant to cefotaxime or ceftriaxone.
Problematic Beta-Lactamases: An Update
Robert C. Owens, Lautenbach Ebbing in Antimicrobial Resistance, 2007
Beta-lactamases are enzymes produced by the great majority of clinically important bacteria. In addition to their relatively well-known job of destroying antibiotics like penicillins, cephalosporins, and carbapenems, they probably also serve other cellular maintenance roles involving the bacterial cell wall. It is hypothesized that beta-lactamases are distant relatives of bacterial cell wall synthesis and cross-linking enzymes called penicillin-binding proteins, which are the actual targets of beta-lactam antibiotics that we use commonly in the clinical setting (1). In terms of antibiotic resistance, the production of beta-lactamases is most important in Gram-negative bacteria like Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. However, some Gram-positive bacteria also produce beta-lactamases; e.g., penicillin resistance in Staphylococcus aureus is partly mediated by an enzyme called PC1, which the bacterium secretes into the surrounding environment.
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 pathogenic microbial flora and its antibiotic susceptibility pattern in odontogenic infections
Published in Drug Metabolism Reviews, 2019
Paul Andrei Tent, Raluca Iulia Juncar, Florin Onisor, Simion Bran, Antonia Harangus, Mihai Juncar
Bacterial resistance to beta-lactams is due to production of beta-lactamase, alteration of penicillin-binding proteins (PBPs) and barriers to target sites (Kuriyama et al. 2000). The production of beta-lactamase is extremely important in the case of polymicrobial infections in particular, because this also protects beta-lactamase non-producing bacteria, thus preventing the action of beta-lactams on an increased number of strains (Brook 1988; Newman and Goodman 1989; Lewis et al. 1995; Sandor et al. 1998). The main beta-lactamase-secreting microorganisms in head and neck infections of odontogenic origin are Prevotella intermedia and Fusobacterium nucleatum (Appelbaum et al. 1990; Könönen et al. 1997; van Winkelhoff et al. 1997; Kuriyama et al. 2000). The mechanism of alteration of penicillin-binding proteins (PBPs) is characteristic of the Streptococcus species. Six classes of penicillin-binding proteins susceptible to genetic alteration are described: PBP1a, PBP1b, PBP2a, PBP2b, PBP2x, and PBP3 (Sauvage et al. 2008; Chardin et al. 2009). Concomitant alteration of PBP2b, PBP2x, and PBP1a in the same bacterial strain can lead to high levels of resistance to antibiotics (Zapun et al. 2008). The altered genes of penicillin-binding proteins are transmitted to other bacterial strains by intraspecific and interspecific lateral gene transfer, resulting in a high general rate of resistance to antibiotics in the microbiocenosis concerned (Barcus et al. 1995; Zapun et al. 2008; Chardin et al. 2009).
Community-acquired pneumonia: aetiology, antibiotic resistance and prospects of phage therapy
Published in Journal of Chemotherapy, 2020
Md. Moinuddin Sheam, Shifath Bin Syed, Zulkar Nain, Swee- Seong Tang, Dipak Kumar Paul, Kazi Rejvee Ahmed, Sudhangshu Kumar Biswas
Genetic transformation in S. pneumoniae results in alteration of penicillin-binding proteins (PBPs), leading to chemically unusual cell wall structure compared to penicillin-susceptible strains.30 Most importantly, the mortality rate due to penicillin-resistant strains is remarkably higher (38%) than the penicillin-susceptible strains of S. pneumonia (24%).31 In patients with respiratory tract infection, a fluoroquinolone-resistant S. pneumoniae acquired resistance to that particular antibiotic through the sequential mutation of its topoisomerase IV (parC) or DNA gyrase (gyrA) encoding genes.32 Likewise, quinolone-resistant S. pneumoniae has been emerged due to mutation in drug targets such as parC and gyrA genes.16 Furthermore, up to 40% of S. pneumoniae isolates are resistant to macrolides, while about 22% isolates are resistant to clindamycin. In Lithuania, 21.3% of S. pneumoniae strains isolated from children with respiratory tract infection showed resistance to erythromycin.33S. pneumoniae resistance to erythromycin is mediated by erm (B) gene, which encodes rRNA erythromycin resistance methylase that causes target modification. In addition, an active efflux pump is associated with the erythromycin resistance and mef (A) gene is associated with this mechanism.34
Related Knowledge Centers
- Bacteria
- Cell Wall
- Escherichia Coli
- Glutamine Synthetase
- Peptidoglycan
- Protein
- Beta-Lactam Antibiotics
- Tabtoxinine Β-Lactam
- Dd-Transpeptidase
- Filamentation