‘β-Lactams’ as β-lactamase inhibitors

Cole, M.

doi:10.1098/rstb.1980.0039

Cited by 25 publications

(1 citation statement)

References 34 publications

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“…The hunt for β-lactamase inhibitors began in the late 1960s 5 when bacterial β-lactamases developed and threatened the use of penicillin. The first β-lactamase inhibitors were identified in 1976, and they were olivanic acids, which are natural products of the Gram-positive bacterium Streptomyces clavuligerus.…”

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Genomic analysis of Carbapenem-resistance conferring genes in Klebsiella pneumoniae

Subramanian¹

2023

Preprint

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Carbapenems are considered for treating Klebsiella pneumoniae and other Enterobacteriaceae infections, especially if they are not susceptible to other generally prescribed antibiotics, i.e., if they show resistance. In such cases, antibiotic activity decreases, and most patients succumb to the infection. A better understanding of the disease pattern and resistance mechanisms could be gained by magnifying the genes that confer resistance to antibiotics. Therefore, studying the genes that confer resistance to carbapenems and any other antibiotics for that matter is indispensable for coming up with improved treatment options. This study included the analyses of co-resistance patterns between resistance genes-between drug classes and within the carbapenem-resistant genes, genomic context analysis of highly expressed carbapenem-resistant genes, and phylogenetic study of OXA-producing genes, plasmid incompatibility identification, and sequence type identification using MLST. The presence of ESBLs, MBLs, and SBLs across the downloaded genomes was studied. SHV-producing genes were found to co-occur with most of the resistant genes belonging to different drug classes. The plasmid incompatibility type IncFIB was found to be common among the highly expressed genes, and most of these genes were flanked by different families of insertion sequence (IS) elements. MLST study suggested that the presence of sequence types ST-11, ST-14, and ST-147 was common in the downloaded set of genomes.

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Genomic analysis of Carbapenem-resistance conferring genes in Klebsiella pneumoniae

Subramanian¹

2023

Preprint

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β‐Lactamase Inhibitors

Stam

2000

Kirk-Othmer Encyclopedia of Chemical Technology

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The antibacterial effectiveness of penicillins, cephalosporins, and other β‐lactam antibiotics depends on the inactivation of transpeptidases involved in bacterial cell wall synthesis. Bacteria that are resistant to β‐lactam antibiotics often produce enzymes called β‐lactamases that inactivate the antibiotics by catalyzing the hydrolytic opening of the β‐lactam ring to give products devoid of antibacterial activity. One approach to combating antibiotic resistance caused by β‐lactamase is to inhibit the enzyme. Effective combinations of enzyme inhibitors with β‐lactam antibiotics such as penicillins or cephalosporins result in a synergistic response, lowering the minimal inhibitory concentration (MIC) by a factor of four or more for each component. However, pharmacokinetics, stability, ability to penetrate bacteria, cost, and other factors are also important in determining whether an inhibitor is suitable for therapeutic use. The most important β‐lactamases to inhibit clinically are the gram‐positive penases, the gram‐negative TEM, which are Richmond‐Sykes type III, and the gram‐negative chromosomal cephalosporinases–cephases which are Richmond‐Sykes type I. These enzymes may be referred to as penase, TEM(III), and cephase(I). These clinically important β‐lactamases are serine proteases that form an acyl enzyme intermediate with β‐lactam substrates and β‐lactam‐derived β‐lactamase inhibitors. A number of β‐lactamase‐resistant penicillins and cephalosporins were found to be β‐lactamase inhibitors. No clinically useful inhibitors have been identified from this class. Clavulanic acid has only weak antibacterial activity, but is a potent irreversible inhibitor for many clinically important β‐lactamases, including penases and Richmond‐Sykes types II, III, IV, V, VI ( Bacteroides ). Carbapenems are another class of natural product β‐lactamase inhibitors. Many penem β‐lactamase inhibitors are potent antibacterials. Penicillanic acid sulfone, (2( S )‐ cis )‐3,3‐dimethyl‐7‐oxo‐4,4‐dioxide‐4‐thia‐1‐azabicyclo [3.2.0]heptane‐2‐carboxylic acid (sulbactam) ( , ), C 8 H 11 NO 5 S, is a weak antibacterial, but is a potent irreversible inactivator of many β‐lactamases, including penases and Richmond‐Sykes type II, III, IV, V, and VI ( Bacteroides ) β‐lactamases. Sulbactam is better than clavulanic acid against type I cephases, and synergy is observed for combinations of many penicillins and cephalosporins. Because sulbactam is not well absorbed orally, prodrug forms have been developed. Numerous other penicillin sulfones have been reported to be β‐lactamase inhibitors. Among penam β‐lactamase inhibitors, of 6‐β‐bromopenicillanic acid, a potent inhibitor, has progressed to clinical trials. Although a broad range of β‐lactamase inhibitors has been discovered, only clavulanic acid and sulbactam have been commercialized. Clavulanic acid manufactured by SmithKline Beecham is sold as an oral and parenteral product in combination with amoxicillin under the trade name Augmentin. A parenteral product in combination with ticarcillin, C 15 H 16 N 2 O 6 S, has the trade name, Timentin. The oral version of sulbactam in combination with ampicillin, produced by Pfizer is called Unasyn Oral, which is the mutual prodrug sultamicillin. Two sulbactam parenteral products are sold, a combination product with ampicillin called Unasyn and a combination with cefoperazone called Sulperazon. In addition, sulbactam is sold alone for parenteral use with any β‐lactam antibiotic as Betamaze.

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Evolution of ß‐Lactamase Inhibitors

Jackson

1991

Pharmacotherapy

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After the introduction of penicillin G into therapeutics, bacteria became increasingly resistant to this penicillin and subsequent ß‐lactam antibiotics. The major cause of this resistance is ß‐lactamase, an enzyme produced by the bacterium, that destroys the antibiotic before it reaches its target within the bacterial cell. One of the ways to combat this resistance has been the use of ß‐lactamase inhibitors, which protect the antibiotic by inactivating the destructive enzyme before the antibiotic reaches the infection site. At present, at least two ß‐lactamase inhibitors are in clinical use, clavulanic acid and sulbactam, that are effective against most ß‐lactamases, although relatively inactive against class I ß‐lactamases, the cephalosporinases. Newly developed ß‐lactamase inhibitors, however, especially BRL‐42715, show some promise against these enzymes.

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‘β-Lactams’ as β-lactamase inhibitors

Cited by 25 publications

References 34 publications

Genomic analysis of Carbapenem-resistance conferring genes in <i>Klebsiella</i><i> </i><i>pneumoniae</i>

Genomic analysis of Carbapenem-resistance conferring genes in <i>Klebsiella</i><i> </i><i>pneumoniae</i>

β‐Lactamase Inhibitors

Evolution of ß‐Lactamase Inhibitors

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