Targeting host-specific metabolic pathways—opportunities and challenges for anti-infective therapy

Microorganisms can takeover critical metabolic pathways in host cells to fuel their replication. This interaction provides an opportunity to target host metabolic pathways, in addition to the pathogen-specific ones, in the development of antimicrobials. Host-directed therapy (HDT) is an emerging strategy of anti-infective therapy, which targets host cell metabolism utilized by facultative and obligate intracellular pathogens for entry, replication, egress or persistence of infected host cells. This review provides an overview of the host lipid metabolism and links it to the challenges in the development of HDTs for viral and bacterial infections, where pathogens are using important for the host lipid enzymes, or producing their own analogous of lecithin-cholesterol acyltransferase (LCAT) and lipoprotein lipase (LPL) thus interfering with the human host’s lipid metabolism

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

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

Utilization of Existing Human Kinase Inhibitors as Scaffolds in the Development of New Antimicrobials

The prevalence and continuing expansion of drug resistance, both in clinical and community settings represents a major challenge for current antimicrobial therapy. The different approaches for addressing this challenge include (1) identification of novel antibacterials by repurposing of existing drugs originally that historically target host proteins; and (2) effect target switching through modification of existing antimicrobials. The focus of this manuscript is on these drug discovery strategies, with utility for development of new antimicrobials with different modes of action

β-Lactams and Ureas as Cross Inhibitors of Prokaryotic Systems

β-Lactams in the last thirty years have been viewed as universal acylating agents of serine and cysteine enzymes of both prokaryotic and eukaryotic systems. More recently, their use has been propelled by the COVID-19 pandemic, thus broadening their application as inhibitors of viral enzymes. The urea-based drugs have been extensively studied as inhibitors of the aforementioned enzymes. The focus of this review is the last decade’s drug discovery strategies, as well as new strategies that show utility in the expansion of β-lactams and ureas in the development of new antimicrobial and antiviral drugs

Fragment-Based Lead Discovery Strategies in Antimicrobial Drug Discovery

Fragment-based lead discovery (FBLD) is a powerful application for developing ligands as modulators of disease targets. This approach strategy involves identification of interactions between low-molecular weight compounds (100–300 Da) and their putative targets, often with low affinity (KD ~0.1–1 mM) interactions. The focus of this screening methodology is to optimize and streamline identification of fragments with higher ligand efficiency (LE) than typical high-throughput screening. The focus of this review is on the last half decade of fragment-based drug discovery strategies that have been used for antimicrobial drug discovery