Understanding Colistin Resistance Mechanisms in Bacteria

Colistin, a last-resort antibiotic, has become increasingly important in treating multidrug-resistant bacterial infections. However, the rise of colistin resistance poses a challenge to global public health, threatening our ability to combat severe infections effectively.

Understanding how bacteria develop resistance to colistin is essential for developing strategies to address this threat.

Genetic Mutations

Colistin resistance in bacteria often arises from genetic mutations that alter the bacterial cell’s outer membrane. These mutations can modify the lipid A component of lipopolysaccharides, integral to the bacterial outer membrane structure. Such modifications reduce colistin’s ability to bind effectively, diminishing its antibacterial action. For instance, mutations in the pmrA and pmrB genes, part of a two-component regulatory system, can lead to the addition of phosphoethanolamine to lipid A. This alteration decreases the negative charge of the bacterial surface, reducing colistin’s binding affinity.

Mutations in the mgrB gene have also been implicated in colistin resistance. The mgrB gene acts as a negative regulator of the PhoP/PhoQ system, another two-component regulatory system. Mutations or disruptions in mgrB can lead to the upregulation of this system, resulting in similar modifications to the bacterial outer membrane that confer resistance. These genetic changes highlight the adaptability of bacteria in response to antibiotic pressure.

Plasmid-Mediated Resistance

Plasmid-mediated resistance is particularly concerning due to its ability to facilitate the rapid spread of resistance genes across bacterial populations. While genetic mutations are confined to individual bacteria, plasmids can transfer horizontally between different bacteria, escalating the dissemination of resistance traits. The discovery of the mcr-1 gene in 2015 marked a significant milestone in understanding plasmid-mediated resistance. This gene, carried on plasmids, encodes an enzyme that modifies the bacterial outer membrane, reducing colistin’s efficacy.

The presence of the mcr-1 gene on plasmids in various Enterobacteriaceae species, such as Escherichia coli and Klebsiella pneumoniae, exemplifies the potential for widespread resistance. These plasmids often harbor additional resistance genes, leading to multidrug-resistant strains that pose serious treatment challenges. Other variants, like mcr-2 and mcr-3, have been identified, each contributing to the complexity of tracking and controlling the spread of colistin resistance.

Efflux Pumps

Efflux pumps play a role in bacterial resistance to antibiotics, including colistin. These membrane proteins actively expel toxic substances, such as antibiotics, from the bacterial cell, minimizing their intracellular concentration and effectiveness. Unlike genetic mutations or plasmid-mediated resistance, efflux pumps can provide a more generalized defense mechanism against a variety of antimicrobial agents.

The expression of efflux pumps can be upregulated in response to environmental pressures, such as the presence of antibiotics, allowing bacteria to adapt swiftly to hostile conditions. In some Gram-negative bacteria, specific efflux systems, like the AcrAB-TolC in E. coli, have been associated with decreased susceptibility to colistin. These pumps can work synergistically with other resistance mechanisms, compounding the challenge of treating infections caused by resistant strains.

Research into efflux pump inhibitors is ongoing, aiming to develop compounds that can block the action of these pumps and restore the efficacy of antibiotics like colistin. Such inhibitors could potentially be used in combination therapies, targeting multiple resistance mechanisms simultaneously to improve treatment outcomes.

Biofilm Resistance

Biofilms, complex microbial communities encased in a self-produced extracellular matrix, present a barrier to antibiotics, including colistin. Within these structures, bacteria exhibit distinct behaviors and phenotypes compared to their planktonic counterparts, often displaying heightened resistance to antimicrobial agents. This is partly due to the physical barrier that the matrix provides, impeding the penetration of antibiotics and limiting their access to the bacterial cells embedded within.

The biofilm environment fosters a unique microenvironment where bacteria can communicate and coordinate their defense strategies through quorum sensing. This cell-to-cell communication can regulate gene expression, including genes associated with resistance, further complicating treatment efforts. The dense population and proximity of cells within biofilms also facilitate the exchange of genetic material, potentially spreading resistance traits more efficiently.

The resilience of biofilms has implications in clinical settings, particularly in chronic infections and on medical devices where biofilms can establish persistent infections that are difficult to eradicate. Strategies to address biofilm-associated resistance are being explored, including the development of agents that disrupt the biofilm matrix or inhibit quorum sensing, thereby enhancing the penetration and efficacy of antibiotics.