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Biotechnology & Genetic Engineering... 2010β-lactam antibiotics (e.g. penicillins, cephalosporins) are of major clinical importance and contribute to over 40% of the total antibiotic market. These compounds are... (Review)
Review
β-lactam antibiotics (e.g. penicillins, cephalosporins) are of major clinical importance and contribute to over 40% of the total antibiotic market. These compounds are produced as secondary metabolites by certain actinomycetes and filamentous fungi (e.g. Penicillium, Aspergillus and Acremonium species). The industrial producer of penicillin is the fungus Penicillium chrysogenum. The enzymes of the penicillin biosynthetic pathway are well characterized and most of them are encoded by genes that are organized in a cluster in the genome. Remarkably, the penicillin biosynthetic pathway is compartmentalized: the initial steps of penicillin biosynthesis are catalyzed by cytosolic enzymes, whereas the two final steps involve peroxisomal enzymes. Here, we describe the biochemical properties of the enzymes of β-lactam biosynthesis in P. chrysogenum and the role of peroxisomes in this process. An overview is given on strain improvement programs via classical mutagenesis and, more recently, genetic engineering, leading to more productive strains. Also, the potential of using heterologous hosts for the development of novel ß-lactam antibiotics and non-ribosomal peptide synthetase-based peptides is discussed.
Topics: Anti-Bacterial Agents; Cephalosporins; Genetic Engineering; Monobactams; Penicillins; Penicillium chrysogenum; Peptide Synthases; Peroxisomes; beta-Lactams
PubMed: 21415891
DOI: 10.1080/02648725.2010.10648143 -
The Journal of Antimicrobial... Nov 2021Multi-drug resistant (MDR) Gram-negative bacteria represent a growing threat, with an increasing prevalence of carbapenem-resistant Enterobacterales (CRE) infections,... (Review)
Review
Multi-drug resistant (MDR) Gram-negative bacteria represent a growing threat, with an increasing prevalence of carbapenem-resistant Enterobacterales (CRE) infections, for which treatment options are limited. New treatment combinations composed of a β-lactam antibiotic plus a potent β-lactamase inhibitor (BLI) with anti-carbapenemase activity have been developed, including two carbapenem/BLI combinations that are commercially available-meropenem/vaborbactam (Vabomere® in the US, Vaborem® in Europe; Melinta Therapeutics) and imipenem/cilastatin/relebactam (Recarbrio®; Merck Sharp & Dohme), plus one other (meropenem/nacubactam) in early clinical development. This review provides a summary of the preclinical evidence supporting the use of carbapenem/BLI combinations and presents the clinical evidence across a range of MDR Gram-negative infections, with a focus on the use of meropenem/vaborbactam. All three BLIs have shown in vivo activity against Klebsiella pneumoniae carbapenemase and other class A carbapenemases. In 2019, meropenem/vaborbactam was listed in the WHO's list of essential medicines, because of its activity against priority 1 antibiotic-resistant pathogens. Meropenem/vaborbactam has considerable in vitro and in vivo activity against CRE, and in vitro evidence showing a low potential for resistance at clinically relevant doses. In randomized trials, meropenem/vaborbactam was non-inferior to piperacillin/tazobactam in patients with complicated urinary tract infection and more effective than the best-available treatment in patients with serious CRE infections. Meropenem/vaborbactam is well tolerated and, based on clinical experience, demonstrated lower toxicity compared with the combination regimens that have previously been the standard of care. In conclusion, carbapenem/BLI combinations represent an important therapeutic strategy in patients with MDR Gram-negative infections.
Topics: Anti-Bacterial Agents; Carbapenems; Drug Resistance, Multiple, Bacterial; Humans; Monobactams; beta-Lactamase Inhibitors
PubMed: 34849998
DOI: 10.1093/jac/dkab353 -
ACS Infectious Diseases Oct 2022The discovery of β-lactam (BL) antibiotics in the early 20th century represented a remarkable advancement in human medicine, allowing for the widespread treatment of... (Review)
Review
The discovery of β-lactam (BL) antibiotics in the early 20th century represented a remarkable advancement in human medicine, allowing for the widespread treatment of infectious diseases that had plagued humanity throughout history. Yet, this triumph was followed closely by the emergence of β-lactamase (BLase), a bacterial weapon to destroy BLs. BLase production is a primary mechanism of resistance to BL antibiotics, and the spread of new homologues with expanded hydrolytic activity represents a pressing threat to global health. Nonetheless, researchers have developed strategies that take advantage of this defense mechanism, exploiting BLase activity in the creation of probes, diagnostic tools, and even novel antibiotics selective for resistant organisms. Early discoveries in the 1960s and 1970s demonstrating that certain BLs expel a leaving group upon BLase cleavage have spawned an entire field dedicated to employing this selective release mechanism, termed BLase-mediated fragmentation. Chemical probes have been developed for imaging and studying BLase-expressing organisms in the laboratory and diagnosing BL-resistant infections in the clinic. Perhaps most promising, new antibiotics have been developed that use BLase-mediated fragmentation to selectively release cytotoxic chemical "warheads" at the site of infection, reducing off-target effects and allowing for the repurposing of putative antibiotics against resistant organisms. This Review will provide some historical background to the emergence of this field and highlight some exciting recent reports that demonstrate the promise of this unique release mechanism.
Topics: Anti-Bacterial Agents; Humans; Monobactams; beta-Lactamases
PubMed: 36048623
DOI: 10.1021/acsinfecdis.2c00315 -
The Journal of Antibiotics Feb 1987New monobactams, PB-5266 A, B and C were isolated from the culture filtrate of Cytophaga johnsonae PB-5266 by various types of column chromatography and preparative...
New monobactams, PB-5266 A, B and C were isolated from the culture filtrate of Cytophaga johnsonae PB-5266 by various types of column chromatography and preparative reverse phase HPLC. PB-5266 A, B and C exhibited weak antibacterial activity against a sensitive mutant of Escherichia coli to beta-lactam antibiotics.
Topics: Anti-Bacterial Agents; Biochemical Phenomena; Biochemistry; Chromatography; Cytophaga; Monobactams
PubMed: 3570960
DOI: 10.7164/antibiotics.40.135 -
Antimicrobial Agents and Chemotherapy Sep 1982Monobactams containing 3 beta-aminothiazolyl oxime side chains (SQ 81,377, SQ 81,402, azthreonam, and SQ 26,917) have poor affinities for the broad-spectrum...
Monobactams containing 3 beta-aminothiazolyl oxime side chains (SQ 81,377, SQ 81,402, azthreonam, and SQ 26,917) have poor affinities for the broad-spectrum beta-lactamases TEM-2 and K1. Addition of a 4-methyl substituent significantly increased stability to hydrolysis by these enzymes. P99 cephalosporinase from Enterobacter cloacae was strongly inhibited by the monobactams. Interaction of azthreonam with the P99 enzyme in equimolar concentrations resulted in a single covalent complex which retained less than 3% catalytic activity. On incubation, enzymatic activity was slowly regained. Chromatographic studies of the incubation mixtures revealed the presence of a single ring-opened product. It is concluded that monobactams act as poor substrates for broad-spectrum beta-lactamases and tight-binding competitive substrates for the P99 beta-lactamase.
Topics: Anti-Bacterial Agents; Aztreonam; Bacteria; Hydrolysis; Kinetics; beta-Lactamase Inhibitors; beta-Lactamases
PubMed: 6982680
DOI: 10.1128/AAC.22.3.414 -
Mini Reviews in Medicinal Chemistry 2020A monocyclic ring in their structure characterizes monobactams, a subclass of β-lactam antibiotics. Many of these compounds have a bactericidal mechanism of action and... (Review)
Review
A monocyclic ring in their structure characterizes monobactams, a subclass of β-lactam antibiotics. Many of these compounds have a bactericidal mechanism of action and acts as penicillin and cephalosporins, interfering with bacterial cell wall biosynthesis. The synthesis of novel β-lactams is an emerging area of organic synthesis research due to the problem of increasing bacterial resistance to existing β -lactam antibiotics, and, in this way, new compounds have been presented with several structural modifications, aiming to improve biological activities. Among the biological activities studied, the most outstanding are antibacterial, antitubercular, anticholesterolemic, anticancer, antiinflammatory, antiviral, and anti-enzymatic, among others. This review explores the vast number of works related to monocyclic β-lactams, compounds of great importance in scientific research.
Topics: Anti-Infective Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Antitubercular Agents; Molecular Structure; Monobactams
PubMed: 32560602
DOI: 10.2174/1389557520666200619114820 -
Orthopedics Jul 1996
Review
Topics: Adult; Aged; Aged, 80 and over; Arthritis, Gouty; Arthritis, Infectious; Aztreonam; Escherichia coli Infections; Female; Humans; Male; Middle Aged; Monobactams; Nafcillin; Penicillins; Staphylococcal Infections
PubMed: 8823821
DOI: No ID Found -
Antimicrobial Agents and Chemotherapy Mar 1991Carumonam and BO-1166 (cis configuration) were inactivated by beta-lactamase of Morganella morganii more rapidly than were aztreonam and BO-1165 (trans configuration),... (Comparative Study)
Comparative Study
Carumonam and BO-1166 (cis configuration) were inactivated by beta-lactamase of Morganella morganii more rapidly than were aztreonam and BO-1165 (trans configuration), as demonstrated by spectrophotometric analysis and microbiological assay. An active enzyme was recovered more rapidly from the inactivated enzyme-monobactam complex derived from the cis form of monobactams than from the complex derived from the trans form of monobactams. This result suggests that the configuration at the 3,4 position on the azetidinone ring of monobactams, together with the chemical structure of the side chains attached to the azetidinone ring, may play an important role in the stability of monobactams to the beta-lactamase of M. morganii.
Topics: Aztreonam; Cell Line; Gram-Negative Bacteria; Hydrolysis; Microbial Sensitivity Tests; Monobactams; Stereoisomerism; Structure-Activity Relationship; beta-Lactamases
PubMed: 2039196
DOI: 10.1128/AAC.35.3.458 -
Antimicrobial Resistance and Infection... Apr 2023Rapid emergence of multidrug resistant Staphylococcus aureus has resulted to difficulty in treatment of infections caused by such strains. The aim of this meta-analysis... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Rapid emergence of multidrug resistant Staphylococcus aureus has resulted to difficulty in treatment of infections caused by such strains. The aim of this meta-analysis study was to determine the pooled prevalence of resistance of S. aureus to different antibiotics in Nigeria.
METHODS
Literature search for studies was done using Google scholar, PubMed, Science direct, and African Journal Online. The prevalence of S. aureus resistance to different antibiotics was evaluated using the meta-analysis proportion command in MedCalc software version 20.0 adopting a rand effect model. I statistic and Egger test in MedCalc was used to evaluate the heterogeneity and the presence of publication bias among studies respectively.
RESULTS
A total of 40, 682 studies were retrieved through the database search of which 98 studies met the study inclusion criteria. Prevalence of resistance of S. aureus to different antibiotics ranges from 13 to 82%. Results showed a very high degree of resistance to penicillin G (82% [95% confidence interval (CI) 61%, 0.96%]), cloxacillin (77% [95% CI 64%, 88%]), amoxacillin (74% [95% CI 66%, 81%]), cefuroxime (69% [95% CI 51%, 85%]), ampicillin (68% [95% CI 53%, 81%]). Moderately resistance to erythromycin (47% [95% CI 40%, 53%]), chloramphenicol (47% [95% CI 37%, 56%]), methicillin (46% [95% CI 37%, 56%]), ofloxacin (24% [95% CI 18%, 31%]) and rifampicin 24% [95% CI 6%, 48%]). Low resistance was observed in vancomycin 13% (95% CI 7%, 21%). For each individual meta-analysis, high heterogeneity was observed with I range (79.36-98.60%) at p-values ≤ 0.01). Egger's tests for regression intercept in funnel plots indicated no evidence of publication bias.
CONCLUSION
This meta-analysis study established that S. aureus in Nigeria has developed resistance to commonly used antibiotics such as the beta-lactam class antibiotics, sulphonamides, tetracyclines, chloramphenicol, and vancomycin. Hence it is imperative to develop programs to promote rational use of antimicrobial agents, infection prevention and control to reduce the incidence of antimicrobial resistance.
Topics: Humans; Anti-Bacterial Agents; Staphylococcus aureus; Vancomycin; Methicillin-Resistant Staphylococcus aureus; Prevalence; Nigeria; Staphylococcal Infections; Chloramphenicol; Monobactams
PubMed: 37098614
DOI: 10.1186/s13756-023-01243-x -
Expert Review of Anti-infective Therapy Apr 2023Continuous infusion (CI) of beta-lactam antibiotics may be of benefit in some patients, particularly those with severe infections. However, most studies have been small... (Review)
Review
INTRODUCTION
Continuous infusion (CI) of beta-lactam antibiotics may be of benefit in some patients, particularly those with severe infections. However, most studies have been small and conflicting results have been reported. The best available evidence on clinical outcomes of beta-lactam CI comes from systematic reviews/meta-analyses that integrate the available data.
AREAS COVERED
A search of PubMed from inception to the end of February 2022 for systematic reviews of clinical outcomes with beta-lactam CI for any indication identified 12 reviews, all of which focused on hospitalized patients, most of whom were critically ill. A narrative overview of these systematic reviews/meta-analyses is provided. No systematic reviews evaluating the use of beta-lactam CI for outpatient parenteral antibiotic therapy (OPAT) were identified, as few studies have focused on this area. Relevant data are summarized, and consideration is given to issues that need to be addressed when using beta-lactam CI in the setting of OPAT.
EXPERT OPINION
Evidence from systematic reviews supports a role for beta-lactam CI in the treatment of hospitalized patients with severe/life-threatening infections. Beta-lactam CI can play a role in patients receiving OPAT for severe chronic/difficult-to-treat infections, but additional data are needed to clarify its optimal use.
Topics: Humans; Anti-Bacterial Agents; Outpatients; Systematic Reviews as Topic; beta-Lactams; Monobactams
PubMed: 36867528
DOI: 10.1080/14787210.2023.2184347