Beta-lactams and Beta-lactamase-inhibitors in current- or potential-clinical practice: A comprehensive update

Abstract

The use of successive generations of beta-lactams has selected successive generations of beta-lactamases including CTX-M ESBLs, AmpC beta-lactamases, and KPC carbapenamases in Enterobacteriaceae. Moreover, this cephalosporin resistance, along with rising resistance to fluoroquinolones, is now driving the use of carbapenems and unfortunately the carbapenem resistance has emerged markedly, especially in Acinetobacter spp. due to OXA- and metallo-carbapenemases. The industry responded to the challenge of rising resistance and recently developed some novel beta-lactams such as ceftobiprole, ceftaroline etc. and many beta-lactam compounds, including beta-lactamase-inhibitors, such as BMS-247243, S-3578, RWJ-54428, CS-023, SMP-601, NXL 104, BAL 30376, LK 157, and so on are under trials. This review provides the comprehensive accounts of the developments in penicillins, cephalosporins, carbapenems, and beta-lactamase-inhibitors, and the insight about medicinal chemistry, mechanism(s) of action and resistance, potential strategies to overcome resistance due to beta-lactamases, and also the recent advancements in the development of newer beta-lactam compounds; some of which are still under trials and yet to be classified. This review will fill the gap since previously published reviews and will serve as a comprehensive update on the current topic.

Identification of Products of Inhibition of GES-2 β-Lactamase by Tazobactam by X-ray Crystallography and Spectrometry

“…Hence, whereas its formation as a matter of hydrolysis of the imine in compound 7 or species 3 is understood, that it could remain bound to the enzyme is not precedented in the literature. Once compound 6 is released from 3, we detect four additional species (8)(9)(10)(11) by mass spectrometry, each of which contributes to inhibition of the enzyme. Whereas 8 and 9 could be construed also as transiently inhibited species, species 10 and 11 are decidedly contributors to irreversible inhibition.…”

“…The active site is located at the interface of the two domains, formed primarily by ␤-strand B3 (residues 230 -238) and a highly conserved structural motif known as the ⍀-loop (residues 160 -180). The catalytic serine residue (Ser 70 ) is located on a short 3 10 helix at the N terminus of helix H2. Lys 73 , a catalytic residue in class A enzymes, is one turn further on in helix H2, and is hydrogen-bonded through the N atom to the O␥ atom of Ser 70 .…”

New Treatment Options against Gram-negative Organisms

“…Among these agents, BLI-489 is the compound with the most promising clinical data. It has shown activity against molecular class A, C and D enzymes, including ESBL as well as class C β-lactamases; some strains that were class C or ESBL producers, classifi ed as non-susceptible to piperacillin/ tazobactam, were found to be susceptible to piperacillin/ BLI-489 [24].…”

MOLECULAR AND MORPHOLOGICAL IDENTIFICATION OF STREPTOMYCES SP. NRC-88 NOVA SPECIES AS Β-Lactamase INHIBITOR FOR PHARMACEUTICAL APPLICATION

“…Not long after the use of the β-lactam antibiotics, the resistance of β-lactam antibiotics is associated with inactivation of the β-lactam structure due to the opening of the β-lactam ring by β-lactamase produced by bacteria [3]. Microorganisms which are impervious to specific antitoxins are progressively causing difficult issues in the treatment of irresistible maladies [4].…”

“…CA is a powerful inhibitor of an extensive variety of β-lactamase from pathogenic living beings which are in charge of the defense of microorganisms against β-lactam antibiotics [3]. CA or clavulanate, is commercially used along with amoxicillin or ticarcillin (augmentin), which is β-lactam antibiotics with high levels of antibacterial activity and this combination has been listed as an important and very successful antibacterial agents in preventing infections due to Gram-positive (Staphylococcus sp.)…”