Medicinal Chemistry of β‐Lactam Antibiotics

Abstract

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.

Stannyl phosphaketene as a synthon for phosphorus analogues of β-lactams

“…24 For example, penicillin, penem, carbapenem, cephalosporin, cephamycin, monobactam, and their derivatives all feature 2-azetidionone cores. 25,26 Focusing attention on the phosphorus analogue of β-lactams, we note that such species scarcely appear in the literature. Ionkin et al isolated the keto-form compound of 1,2-dihydrophosphate from the pyrolysis of its corresponding silyl enol-form.…”

On drug discovery against infectious diseases and academic medicinal chemistry contributions

“…Concerning another class of "old" drugs, and as depicted in Figure 9 with the (few) structures 49-61, the many generations of β-lactams used in human medicine is certainly one more illustration of how medicinal chemistry proceeds across decades of research. As well described in book chapters [302,303], these antibiotics owe their existence to the isolation of naturally occurring substances along with their (bio)transformations to improve their production and/or their human pharmacology. Moreover, preparing fully artificial β-lactam analogues is also an active research field since, for instance aztreonam (61), is produced by total synthesis [304,305].…”

“…As seen in Figure 9, the rate of new β-lactams approved for human use has slowed down but it has yet to stop. Could the use of very recent chemistry allow to go beyond the current [303,[306][307][308][309][310] state of the art? Aside from these rather thoroughly investigated β-lactam antibiotics (more than 40,000 tons are produced every year), one could consider the much less studied novobiocin (62) depicted in Figure 10.…”

Degradation of Penicillinic Antibiotics and β‐Lactamase Enzymatic Catalysis in a Biomimetic Zn‐Based Metal–Organic Framework

“…β‐Lactam antibiotics ‐including penicillins, cephalosporins and cephamycins, monobactams, carbapenems and carbacephems‐ are the most commonly used group of antibiotics against bacterial infections [1] . They all have in common the presence of a four‐membered β‐lactam ring in their chemical structure, which lies at the origin of their antibacterial properties [1] .…”

“…β‐Lactam antibiotics ‐including penicillins, cephalosporins and cephamycins, monobactams, carbapenems and carbacephems‐ are the most commonly used group of antibiotics against bacterial infections [1] . They all have in common the presence of a four‐membered β‐lactam ring in their chemical structure, which lies at the origin of their antibacterial properties [1] . However, this feature also represents the main drawback of this family of antibiotics as certain bacteria are capable to, among other resistance mechanisms, secrete β‐lactamase enzymes that are capable to inactivate most β‐lactam antibiotics by degrading the mentioned four‐membered ring [2] …”