Antibiotics with novel mode of action as new weapons to fight antimicrobial resistance

Antimicrobial resistance (AMR) is a major public health issue, causing 5 million deaths per year. Without any action plan, AMR will be in a near future the leading cause of death ahead of cancer. AMR comes from the ability of bacteria to rapidly develop and share resistance mechanisms towards current antibiotics, rendering them less effective. To circumvent this issue and avoid the phenomenon of cross-resistance, new antibiotics acting on novel targets or with new modes of action are required. Today, the pipeline of potential new treatments with these characteristics includes promising compounds such as gepotidacin, zoliflodacin, ibezapolstat, MGB-BP-3, CRS-3123, afabicin and TXA-709, which are currently in clinical trials, and lefamulin, which has been recently approved by FDA and EMA. In this review, we report the chemical synthesis, mode of action, structure-activity relationships, in vitro and in vivo activities as well as clinical data of these eight small molecules listed above.