Molecular Targets of β-Lactam-Based Antimicrobials: Beyond the Usual Suspects

Abstract

The common practice in antibacterial drug development has been to rapidly make an attempt to find ever-more stable and broad-spectrum variants for a particular antibiotic, once a drug resistance for that antibiotic is detected. We are now facing bacterial resistance toward our clinically relevant antibiotics of such a magnitude that the conversation for antimicrobial drug development ought to include effective new antibiotics with alternative mechanisms of action. The electrophilic β-lactam ring is amenable for the inhibition of different enzyme classes by a suitable decoration of the core scaffold. Monocyclic β-lactams lacking an ionizable group at the lactam nitrogen exhibit target preferences toward bacterial enzymes important for resistance and virulence. The present review intends to draw attention to the versatility of the β-lactams as antimicrobials with “unusual” molecular targets.

Toxicity of β-Lactam Antibiotics: Pathophysiology, Molecular Biology and Possible Recovery Strategies

“…There are two types of β-lactamases: (a) serine-β-lactamases and (b) MBLs. Serine-β-lactamases comprise ESBLs and carbapenemases that hydrolyse carbapenem antibiotics and cephalosporins [2,20]. We can suice to say that the most common mechanism for drug resistance to β-lactam antibiotics is bacterial synthesis of β-lactamases.…”

“…Over the years, countless penicillin derivatives have been produced including penicillins, cephalosporins, carbapenems, oxapenems, oxacephams as well as monocyclic, spirocyclic and multicyclic ring systems [2]. The irst β-lactam antibiotic was 'penicillin G' in the beginning of 1940s [1].…”

“…Developing more stable and more efective strategies is the key factor. For instance, ampicillin/sulbactam, amoxicillin/clavulanate, ticarcillin/clavulanate and piperacillin/tazobactam are the most used β-lactamase inhibitor combinations for clinicians [2]. Moreover, the selection of right β-lactam antibiotics for patients who have an antibiotic allergy is important.…”

“…β-lactam or β-lactamase inhibitor antibiotics are substances that disrupt bacterial cell-wall formation via penicillin-binding proteins (PBPs) where they bind covalently at the terminal step of peptidoglycan cross-linking in bacteria [1]. The irst generation of β-lactam antibiotics were penicillins, followed by cephalosporins; later carbapenems and monocyclic β-lactams that have been recently introduced and are currently in service for the treatment of infectious disease caused by pathogenic bacteria [2]. However, following the occurrence of resistance to the penicillin, new β-lactam antibiotics are being researched for enhancing the spectrum eiciency against the β-lactam-resistant bacteria [3].…”

Novel drug delivery systems to combat antimicrobial resistance

“…Only type I adjuvants, which work against β-lactamase and extended-spectrum β-Lactamases (ESBLs), are clinically used. β-lactamase activity plays a crucial role in bacterial resistance against antibiotics containing β-lactam ring [45]. β-lactamase breaks the β-lactam ring open, rendering the antibiotic incapable of its activity.…”