Binding of monobactams to penicillin-binding proteins of Escherichia coli and Staphylococcus aureus: relation to antibacterial activity

Georgopapadakou, Nafsika H.; Smith, Sarah M.; Cimarusti, Christopher M.; Sykes, R. B.

doi:10.1128/aac.23.1.98

Cited by 34 publications

(17 citation statements)

References 23 publications

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“…DISCUSSION AZT, is a member of a new class of monocyclic synthetic ,-lactam agents with in vitro activity against the vast majority of gram-negative bacteria, including members of the family Enterobacteriaceae and most isolates of Pseudomonas aeruginosa. The compound is inactive against aerobic gram-positive and anaerobic bacteria, has a high affinity for essential PBP 3 of gram-negative bacilli, and is stable to a wide range of f3-lactamases (1,4,7,15,19,21,23,35).…”

Section: Resultsmentioning

confidence: 99%

Evaluation of aztreonam in the treatment of severe bacterial infections

Romero-Vivas¹,

Rodríguez‐Créixems²,

Bouza³

et al. 1985

Antimicrob Agents Chemother

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Aztreonam (AZT) is a member of a new class of monocyclic synthetic P-lactam agents with in vitro activity against the vast majority of gram-negative bacteria, including members of the family Enterobacteriaceae and most isolates of Pseudomonas aeruginosa. The compound is inactive against aerobic, gram-positive and anaerobic bacteria. It is likely that this selective spectrum of action causes minimal disturbance of normal human fecal flora, thus decreasing the risk of overgrowth of enterococci and other resistant strains (12,15,21,23,34,35).High levels of AZT in serum can be obtained with a 1-g parenteral dose, protein binding is about 56%, and the terminal half life in serum is 1.7 h. AZT is not metabolized in the body, renal excretion occurs by glomerular filtration, and about 65% of the antibiotic is recovered unchanged from the urine (18,29,(31)(32)(33).With these considerations in mind, we evaluated the clinical efficiency, tolerance, and toxicity of AZT in the treatment of 46 patients with 50 episodes of severe bacterial infections. MATERIALS AND METHODSPatients. Forty-six hospitalized patients were selected for the study. All had clear symptoms and signs of infection and microorganisms supposedly responsible for the infection had been identified within the previous 48 h.We considered as urinary tract infection (UTI) the isolation of significant bacteriuria (>105 CFU/ml) in the presence of related clinical symptoms. Our single case with respiratory tract infection was a patient with pneumonia defined by the presence of fever and pulmonary infiltrates and the isolation of a single pathogen from an endotracheal aspiration. Our diagnoses of osteomyelitis were supported by the presence of concomitant bacteremia in one case, with the isolation of the responsible microorganisms during surgical procedures in six patients and direct isolation from an open * Corresponding author.

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Section: Resultsmentioning

confidence: 99%

Evaluation of aztreonam in the treatment of severe bacterial infections

Romero-Vivas¹,

Rodríguez‐Créixems²,

Bouza³

et al. 1985

Antimicrob Agents Chemother

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“…Under these conditions, PBP 4 was somewere consistent with the observations made for the same times detected. The occasional difficulty in PBP 2 elucidacompounds in aerobic gram-negative rod-shaped bacteria (3, tion and the unpredictable appearance of PBP 4 were not due 7,11,12,14,23). to the time (in the bacterial growth cycle) of cell harvest for Affinity of PBPs for I8-lactam compounds.…”

Section: Methodsmentioning

confidence: 99%

Properties of the penicillin-binding proteins of four species of the genus Bacteroides

Piddock¹,

Wise²

1986

Antimicrob Agents Chemother

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The peniciilin-binding proteins (PBPs) of four species of the genus Bacteroides were examined in cell envelope preparations from exponentially growing cultures and intact cells. Upon examination by sodium dodecyl sulfate-polyacrylamide electrophoresis, three major high-molecular-weight PBPs (molecular weight, 58,000 to 82,000) were resolved, and low-molecular-weight PBPs were seen in all strains except Bacteroidesfragilis. The sporadic appearance of PBP 4 in B. fragilis (molecular weight, approximately 45,000) was shown not to be influenced by the concentration of free iron available in the medium or by the stage of growth at which the batch culture was harvested. No PBP that was inhibited by an aerobic environment was demonstrated. The affinity of 35 ,B-lactam antibiotics for the PBPs from envelope preparations was examined and correlated with the morphological response. Most compounds bound initially to PBP 2 and then PBP 1, correlating with a primary response of filamentation and then spheroplasting and lysis. Compounds such as clavulanic acid bound to PBP 3 at concentrations causing round cells. Based on the data from this study, it is proposed that the three high-molecular-weight PBPs of Bacteroides fragilis, Bacteroides vulgatus, Bacteroides thetaiotaomicron, and Bacteroides ovatus correlate to the three high-molecular-weight PBPs of Escherichia coli and that the PBPs of Bacteroides species perform the same enzymic role in cell wall biosynthesis as their counterparts in E. coli. Therefore, the components of PBP 1 are involved in cell elongation, PBP 2 is involved in septum formation, and PBP 3 is involved in maintenance of cell shape (i.e., PBP 2 in Bacteroides spp. = PBP 3 in E. coli, and PBP 3 in Bacteroides spp. = PBP 2 in E. coli).Species of the genus Bacteroides are commonly encountered in infection, and certain of the species are the anaerobes most resistant to antimicrobial agents (8) and in particular the P-lactam class of antibiotics, owing to the presence of potent P-lactamases (17,18). The development of 3-lactamase-stable r-lactams has not led to greatly enhanced activity for Bacteroides species, and the recent emergence of resistance to cefoxitin, which is not attributable to classical P-lactamase activity (2, 6), has renewed interest in the mechanism of action of 1-lactams in Bacteroides species.

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“…The cephalothin homolog had the same spectrum as cephalothin but was less potent, while the cefoperazone homolog was very similar in potency to cefoperazone against gram-negative organisms (60). These patterns of activity generally followed the affinities of each agent for the lethal PBPs in gram-positive and gram-negative organisms (60). Some of the best activity against gram-negative organisms was obtained by adding the aminothiazole oxime side chain (Fig.…”

Section: Preclinical Testing Stages Discovery Of New Antibioticsmentioning

confidence: 98%

“…2). The high activity of aztreonam against gram-negative organisms can be explained by the presence of the aminothiazole oxime moiety, which confers high affinity for the lethal PBPs 3 and la (60,157). The presence of a carboxylic acid function on the oxime side chain was shown to improve activity against Pseudomonas aeruginosa (158).…”

Section: Preclinical Testing Stages Discovery Of New Antibioticsmentioning

confidence: 99%

“…Monobactams have been isolated from fermentations of several bacterial species, and all contain a 2-azetidinone-1-sulfonic acid moiety (Fig. 2) (60,156). The cephalothin homolog had the same spectrum as cephalothin but was less potent, while the cefoperazone homolog was very similar in potency to cefoperazone against gram-negative organisms (60).…”

Section: Preclinical Testing Stages Discovery Of New Antibioticsmentioning

confidence: 99%

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Discovery and development of new antimicrobial agents

Gootz

1990

Clin Microbiol Rev

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The unprecedented growth in the number of new antibiotics over the past two decades has been the result of extensive research efforts that have exploited the growing body of knowledge describing the interactions of antibiotics with their targets in bacterial cells. Information gained from one class of antimicrobial agents has often been used to advance the development of other classes. In the case of beta-lactams, information on structure-activity relationships gleaned from penicillins and cephalosporins was rapidly applied to the cephamycins, monobactams, penems, and carbapenems in order to discover broad-spectrum agents with markedly improved potency. These efforts have led to the introduction of many new antibiotics that demonstrate outstanding clinical efficacy and improved pharmacokinetics in humans. The current review discusses those factors that have influenced the rapid proliferation of new antimicrobial agents, including the discovery of new lead structures from natural products and the impact of bacterial resistance development in the clinical setting. The development process for a new antibiotic is discussed in detail, from the stage of early safety testing in animals through phase I, II, and III clinical trials.

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Binding of monobactams to penicillin-binding proteins of Escherichia coli and Staphylococcus aureus: relation to antibacterial activity

Cited by 34 publications

References 23 publications

Evaluation of aztreonam in the treatment of severe bacterial infections

Evaluation of aztreonam in the treatment of severe bacterial infections

Properties of the penicillin-binding proteins of four species of the genus Bacteroides

Discovery and development of new antimicrobial agents

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