β‐Lactam Antibiotics

Abstract

The β‐lactam classes of antibacterials are preeminent in the treatment of bacterial infection due to their unparalleled clinical efficacy and clinical safety. Following the discovery of the penicillins, successive β‐lactam drug discovery has added the cephalosporin, penem cephamycin, clavulanate, monobactam, nocardicin, and carbapenem subclasses. The driving force behind much of this era of discovery is the staggering ability of pathogenic bacteria to adapt previous generations of the β‐lactam by the acquisition and expression of resistance mechanisms. Although many factors contribute to β‐lactam resistance, alterations to the molecular targets of the β‐lactams (the penicillin binding proteins) and the use of enzymes (the β‐lactamases) capable of the hydrolytic deactivation of the β‐lactams are paramount. This review traces the historical development of β‐lactam drug discovery, with emphasis on the most recent progress in the medicinal chemistry, biochemistry, and microbiology of the β‐lactams leading to the discovery of new generation β‐lactam antibacterials effective against the Gram‐negative and ‐positive bacterial pathogens of current medical concern.

Hydrolytic Mechanism of OXA-58 Enzyme, a Carbapenem-hydrolyzing Class D β-Lactamase from Acinetobacter baumannii

“…Carbapenems such as imipenem and meropenem are ␤-lactam antibiotics with a wide spectrum of activity, initially designed to overcome ␤-lactam resistance because of their stability toward most ␤-lactamases (1,2). However, as a result of selective pressure, these carbapenems have succumbed to the hydrolytic power of ␤-lactamases.…”

“…New carbapenem-hydrolyzing class D ␤-lactamases (CHDLs) 2 are directly associated with outbreaks of carbapenem-resistant Acinetobacter baumannii around the world (8 -11). Carbapenems have been the drug of choice in treatment of multidrug-resistant A. baumannii.…”

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

“…␤-Lactam antibiotics represent more than 65% of the worlds antibiotic market and encompass a range of natural, semisynthetic, and synthetic compounds that include penicillins, cephalosporins, monobactams, carbapenems, and penems (1). They are extensively used in the treatment of a wide variety of infections caused by Gram-negative and Gram-positive bacteria (2).…”

“…They are extensively used in the treatment of a wide variety of infections caused by Gram-negative and Gram-positive bacteria (2). ␤-Lactams kill bacteria by selectively inhibiting enzymes involved in the synthesis of the microbial cell wall, specifically its peptidoglycan component, a uniquely bacterial structure (1). These enzymes, collectively known as penicillin-binding proteins, because of their ability to bind covalently to penicillins (3,4), carry out cross-linking of the bacterial cell wall through polypeptide bridges via a transpeptidation reaction.…”

Synthesis, conformation and antiproliferative activity of isothiazoloisoxazole 1,1-dioxides

“…The field is dominated by the β-lactams (1) [ Figure 1] due to the importance that they have acquired as anti-infective agents. [1][2][3] The corresponding β-sultams (2) are also known and have attracted attention as taurine precursors, 4,5 β-lactamase inhibitors, 6 D,D-peptidase inhibitors, 7 human neutrophil elastase inhibitors, [8][9][10] azoreductase inhibitors, 11 anti-inflammatory agents, 12 potential treatments for alcohol dependency, 13 SPase I inhibitors 14 and ClpP protease inhibitors, 15 and have attracted other mechanistic 16,17 and synthetic efforts. [18][19][20] β-Sultam chemistry been a focus of our research for some time.…”