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