How to spare gut microbiota from antibiotic effects? PK-PD based innovative strategies, target specificity, and molecule-to-medicinal properties

Conventional broad-spectrum antibiotics often disrupt gut microbiota, causing a range of health issues like inflammatory bowel disease (IBD), secondary infections, colorectal cancer, liver disease, cognitive impairment, diabetes, and obesity. While the 'one drug treats all' strategy offers convenience, the long-term consequences of microbiota imbalance caused by such antibiotics can no longer be ignored. Modern antibiotic discovery and development programs must consider the strategies that minimize microbiota disruption to prevent long-term dysbiosis. This article presents, for the first time, a critical analysis of emerging microbiota-sparing pharmacokinetic-pharmacodynamic (PK-PD) based innovative antibacterial therapeutic strategies, such as transporter (BmpD)-mediated selective uptake, selective accumulation driven by efflux deficiency, pathogen-specific and pH-dependent selective cellular absorption, adjuvant facilitated therapy, β-lactamase-directed selectivity, microbiota-conserving immunotherapy, and CRISPR-based phage therapy. It highlights target-specific antibacterial approaches aimed at distinct bacterial pathways, such as lipoprotein transport, fatty acid biosynthesis, protein biosynthesis <i>via</i> methionyl-tRNA synthetase (MetRS), and DNA replication through DNA polymerase IIIC, which can minimize microbiota disruption and antibiotic-associated dysbiosis. Additionally, the discovery of antibacterial clinical candidates, such as afabicin, lolamicin, hygromycin A, cadazolid, and ribaxamase, that exhibit pathogen-specific efficacy with limited gut exposure, has been discussed with an in-depth analysis of their mechanism of actions (MoAs) and specific bacterial targets, molecular structure-to-medicinal insights, and strategic innovations. Collectively, this article provides a perspective for next generation antibacterial drug design and discovery, focusing on innovative strategies, specific biological pathways, and key molecular features that spare gut microbiota while maximizing antibacterial treatment efficacy.