Colistin Resistance in Gram-Negative Bacteria: Mechanisms, Transmission, and Novel Intervention Strategies

Multidrug resistance (MDR) in Gram-negative bacteria is a global issue and needs to be addressed urgently. MDR can emerge through genetic mutations and horizontal gene transfer and deteriorate under antibiotic selective pressure. The emergence of resistance to last-resort antibiotics, which are used to treat MDR bacteria, is of particular concern. Colistin has been recognized as a last-line antibiotic for the treatment of MDR Gram-negative bacterial infections caused by <i>Escherichia coli</i>, <i>Acinetobacter baumannii</i>, <i>Klebsiella pneumoniae</i>, and <i>Pseudomonas aeruginosa</i>. Recently, the increasing reports of colistin resistance pose a significant threat to public health, caused by both acquired and intrinsic mechanisms. The review aimed to elucidate the trends in colistin resistance, the use of colistin in human and veterinary medicine, underlying resistance mechanisms and transmission pathways, and potential mitigation of this emerging threat through novel intervention strategies. Colistin resistance is mediated by plasmid-encoded phosphoethanolamine transferases (<i>mcr-1</i> to <i>mcr-10</i>) and chromosomal lipid A remodeling pathways. In <i>Escherichia coli</i>, resistance involves <i>mcr-1-10</i>, <i>acrB</i> efflux mutations, <i>pmrA/pmrB</i>, <i>arnBCADTEF</i>, and <i>mgrB</i> inactivation. <i>Klebsiella pneumoniae</i> exhibits <i>mcr-1</i>, <i>mcr-8</i>, <i>mcr-9</i>, <i>mgrB</i> disruption and <i>phoP/phoQ-pmrAB</i> activation. <i>Acinetobacter baumannii</i> harbors <i>mcr-1-4</i>, while <i>Salmonella enterica</i> and <i>Enterobacter</i> spp. carry <i>mcr</i> variants with <i>arnBCADTEF</i> induction. Therapeutic options include adjunct strategies such as antimicrobial peptides, nanomaterials, therapeutic adjuvants, <i>CRISPR-Cas9</i>-based gene editing, probiotics, vaccines, and immune modulators to restore susceptibility. This review identified that specific and wide actions are required to handle the growing colistin resistance, including genomic surveillance, tracing novel resistance mechanisms, and the application of alternative management strategies. The One Health approach is considered a key strategy to address this growing issue.