Dataset Information

Total Syntheses of Bulgecins A, B, and C and Their Bactericidal Potentiation of the ?-Lactam Antibiotics.

ABSTRACT: The bulgecins are iminosaccharide secondary metabolites of the Gram-negative bacterium Paraburkholderia acidophila and inhibitors of lytic transglycosylases of bacterial cell-wall biosynthesis and remodeling. The activities of the bulgecins are intimately intertwined with the mechanism of a cobiosynthesized ?-lactam antibiotic. ?-Lactams inhibit the penicillin-binding proteins, enzymes also critical to cell-wall biosynthesis. The simultaneous loss of the lytic transglycosylase (by bulgecin) and penicillin-binding protein (by ?-lactams) activities results in deformation of the septal cell wall, observed microscopically as a bulge preceding bacterial cell lysis. We describe a practical synthesis of the three naturally occurring bulgecin iminosaccharides and their mechanistic evaluation in a series of microbiological studies. These studies identify potentiation by the bulgecin at subminimum inhibitory concentrations of the ?-lactam against three pathogenic Gram-negative bacteria and establish for the first time that this potentiation results in a significant increase in the bactericidal efficacy of a clinical ?-lactam.

SUBMITTER: Tomoshige S

PROVIDER: S-EPMC5996343 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Publications

Total Syntheses of Bulgecins A, B, and C and Their Bactericidal Potentiation of the β-Lactam Antibiotics.

Tomoshige Shusuke S Dik David A DA Akabane-Nakata Masaaki M Madukoma Chinedu S CS Fisher Jed F JF Shrout Joshua D JD Mobashery Shahriar S

ACS infectious diseases 20180507 6

The bulgecins are iminosaccharide secondary metabolites of the Gram-negative bacterium Paraburkholderia acidophila and inhibitors of lytic transglycosylases of bacterial cell-wall biosynthesis and remodeling. The activities of the bulgecins are intimately intertwined with the mechanism of a cobiosynthesized β-lactam antibiotic. β-Lactams inhibit the penicillin-binding proteins, enzymes also critical to cell-wall biosynthesis. The simultaneous loss of the lytic transglycosylase (by bulgecin) and ...[more]

PMID: 29716193

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Project description:Beta-lactam allergy is a common problem in everyday medical practice and is recognized as a major public health issue. Carrying this label frequently leads to the avoidance of all beta-lactam antibiotics, favoring the use of other less preferred classes of antibiotics, that are more expensive and associated with more side effects and increased antimicrobial resistance. Therefore, delabeling a beta-lactam allergy is part of antimicrobial stewardship programs. Herein, we retrospectively examined the clinical records of 576 patients who were referred to our center for a label of allergy to beta-lactam antibiotics and were systematically investigated following a standardized algorithm. Our main aim was to evaluate the frequency of confirmed immediate- and delayed-type allergy to commonly prescribed subclasses of beta-lactam antibiotics (penicillin and cephalosporin), as well as the negative predictive value (NPV) and the sensitivity of skin tests. Our secondary aims were to examine the safety of beta-lactam skin testing and drug challenge. We identified that 260 patients reported a history of immediate reactions, 131 of delayed reactions, and 114 of unknown timing or mechanism of reactions. Following assessment and testing, 86 (18.3%) patients had a confirmed allergy to any beta-lactam antibiotics; 63 (13.4%) with an immediate- and 23 (4.9%) with a delayed-type reaction. Most frequently identified confirmed allergy was to penicillins (65 patients), followed by cephalosporins (21 patients). When immediate-type reactions were examined, NPV of skin tests were 96.3% and 100% for penicillins and cephalosporins, respectively. When delayed reactions were considered, NPV were 91.9 and 87.5% for penicillins and cephalosporins, respectively. Evaluation of the safety of skin tests according to the standardized procedure showed that systemic allergic reactions occurred in only 0.7% of skin tests and in 3.1% of drug challenges. Overall, our data indicate that only 18.3% of patients with a beta-lactam allergy label have a confirmed allergy and non-allergic patients can be safely delabeled through allergic workup based on skin tests and drug challenge. This approach supports the policy of saving second-line antibiotics through a standardized allergy workup.

Dataset Information

Total Syntheses of Bulgecins A, B, and C and Their Bactericidal Potentiation of the ?-Lactam Antibiotics.

Publications

Total Syntheses of Bulgecins A, B, and C and Their Bactericidal Potentiation of the β-Lactam Antibiotics.

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