Multidrug Resistance Pumps as a Keystone of Bacterial Resistance

Abstract

Antibiotic resistance is a global problem of modern medicine. A harbinger of the onset of the postantibiotic era is the complexity and high cost of developing new antibiotics as well as their inefficiency due to the rapidly developing resistance of bacteria. Multidrug resistance (MDR) pumps, involved in the formation of resistance to xenobiotics, the export of toxins, the maintenance of cellular homeostasis, and the formation of biofilms and persistent cells, are the keystone of bacterial protection against antibiotics. MDR pumps are the basis for the nonspecific protection of bacteria, while modification of the drug target, inactivation of the drug, and switching of the target or sequestration of the target is the second specific line of their protection. Thus, the nonspecific protection of bacteria formed by MDR pumps is a barrier that prevents the penetration of antibacterial substances into the cell, which is the main factor determining the resistance of bacteria. Understanding the mechanisms of MDR pumps and a balanced assessment of their contribution to total resistance, as well as to antibiotic sensitivity, will either seriously delay the onset of the postantibiotic era or prevent its onset in the foreseeable future.

Keywords: antibiotics; bacteriophages; biofilms; multidrug resistance (MDR); persisters; pumps; xenobiotics.

Fig. 1.

Schematic representation of the functioning principles for known families of MDR pumps. To date, six families of MDR pumps have been identified. Among them, only the ABC (ATP-binding cassette) family of transporters directly uses ATP energy for transport; the remaining five families are secondary active transporters that use the electrochemical energy of the transmembrane potential: these include the superfamily MFS (major facilitator superfamily), the MATE (multidrug and toxin extrusion) family, the SMR (small multidrug resistance) family, the RND (resistance-nodulation-cell division) superfamily, and the PACE (proteobacterial antimicrobial compound efflux) family.

Fig. 2.

Role of MDR pumps in bacterial cell processes. Pumps can perform both protective function and active attack function, maintain cell homeostasis, and even be receptors that mediate the penetration of bacteriophages into the cell.