Novel Antimicrobials, Drug Delivery Systems and Antivirulence Targets in the Pipeline-From Bench to Bedside

In a fast-paced medical reality, biosciences and bioengineering have become essential components in medical research and development. The aim of this paper is to characterize the recent progresses made in fighting antimicrobial resistance, particularly in relation to WHO's priority pathogens, by providing an in-depth review of novel antimicrobials, drug delivery systems for targeted antimicrobial action and novel antivirulence targets. We systematically searched the ClinicalTrials.gov database to identify clinical trials targeting WHO's priority 1 (critical) pathogens: carbapenem-resistant Acinetobacter baumannii, carbapenem-resistant Pseudomonas aeruginosa, and carbapenem-resistant ESBL-producing Enterobacteriaceae. We identified a limited number of clinical trials, specifically for: one novel betalactamase inhibitor for Acinetobacter spp., one anti-virulence human monoclonal antibody for Pseudomonas spp. and no novel antimicrobials for carbapenem-resistant Enterobacteriaceae. We also performed a review of field literature to exemplify the main applications of drug delivery systems in infectious diseases, particularly in achieving targeted antibiotic distribution, in enhancing local activity with reduced off-target effects, triggered antibiotic release and triggered antibacterial photodynamic therapy. We conclude by presenting novel targets for antivirulence therapeutics that act by disrupting quorum sensing, inhibiting bacterial adherence and biofilm formation, silencing virulence traits and neutralizing bacterial toxins. Furthermore, the main principles of rational antimicrobial use are highlighted, in an effort to describe potential areas for targeted intervention, from diagnostic stewardship to antimicrobial stewardship.