(6R,8S)-(2-benzimidazolyl)hydroxymethylpenicillanic acids as potent antibacterial agents and .BETA.-lactamase inhibitors.

This chapter reviews the history of β‐lactams from the discovery of penicillin in 1928 to the more recently studied and the current trends in the field. The most relevant aspects related to the mechanism of action of β‐lactams are covered, and the various mechanisms of resistance to currently available β‐lactams that bacteria have adopted since the introduction of penicillin are described. A classification of β‐lactamases and their relevance in clinics is also provided. Applications of β‐lactams both in the hospital and in the community are reported, with particular attention to their pharmacokinetic properties, related side effects, and their therapeutic indications. The history and discovery of β‐lactams are described and all major classes are covered: penicillins, cephalosporins, oxacephems, carbacephems, penems, monobactams and nocardicins, carbapenems and trinems, classical (e.g., clavulanic acid, sulbactam, tazobactam), and the more recently disclosed β‐lactamase inhibitors. Several aspects related to the most recent developments in β‐lactams are also covered: new molecules active against difficult Gram‐positive strains or endowed with an antibacterial broad spectrum of action; potent orally active β‐lactams; injectable β‐lactams; and β‐lactamase inhibitors. The chapter concludes with a continuing analysis of the industry‐driven trends and the most recent new application of β‐lactams as inhibitors of protein export in bacteria. Finally, a few very interesting Web addresses and a comprehensive reference list are also provided.

β‐Lactam Antibiotics

Andreotti

Biondi

Modugno

2003

β‐Lactam Antibiotics

Testero

Fisher

Mobashery

2010

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.

Medicinal Chemistry of β‐Lactam Antibiotics

Testero

Llarrull

Fisher

et al. 2021

The β‐lactam class of antibacterials is a cornerstone of human health. For nearly eight decades, their unparalleled clinical efficacy and clinical safety have made the β‐lactam class preeminent in the treatment of bacterial infection. The relatively brief period in human history during which the β‐lactams have exerted this benefit is a period characterized by continuous medicinal chemistry innovation, seen visibly in the progression from the penicillins to the complex ensemble of β‐lactams (now including also cephalosporins, monobactams, and carbapenems) used in the clinic. The key force behind this innovation is the progressive evolution by bacteria of resistance mechanisms. Today, highly resistant bacteria challenge the way medicinal chemists contemplate the creative alteration of β‐lactam structures, the way the pharmaceutical industry develops β‐lactams (and other antibacterial) structures, and the way the medical community uses antibacterials. This article gives a concise summary of the history of the β‐lactams. Its emphasis is recent structural innovation with respect to the β‐lactams, and with respect to structurally related classes that act to preserve the clinical activity of the β‐lactams through inhibition of bacterial β‐lactam‐hydrolyzing, and thus β‐lactam‐deactivating, enzymes. We integrate these chemistry advances with new biological discoveries with respect to the bactericidal mechanism of the β‐lactams and with respect to bacterial resistance mechanisms. The combination of these perspectives is a foundational perspective to guide the medicinal chemistry future of the β‐lactams.