Bacterial Multidrug Efflux Pumps: Much More Than Antibiotic Resistance Determinants

Abstract

Bacterial multidrug efflux pumps are antibiotic resistance determinants present in all microorganisms. With few exceptions, they are chromosomally encoded and present a conserved organization both at the genetic and at the protein levels. In addition, most, if not all, strains of a given bacterial species present the same chromosomally-encoded efflux pumps. Altogether this indicates that multidrug efflux pumps are ancient elements encoded in bacterial genomes long before the recent use of antibiotics for human and animal therapy. In this regard, it is worth mentioning that efflux pumps can extrude a wide range of substrates that include, besides antibiotics, heavy metals, organic pollutants, plant-produced compounds, quorum sensing signals or bacterial metabolites, among others. In the current review, we present information on the different functions that multidrug efflux pumps may have for the bacterial behaviour in different habitats as well as on their regulation by specific signals. Since, in addition to their function in non-clinical ecosystems, multidrug efflux pumps contribute to intrinsic, acquired, and phenotypic resistance of bacterial pathogens, the review also presents information on the search for inhibitors of multidrug efflux pumps, which are currently under development, in the aim of increasing the susceptibility of bacterial pathogens to antibiotics.

Genome Dynamics and Molecular Infection Epidemiology of Multidrug-Resistant Helicobacter pullorum Isolates Obtained from Broiler and Free-Range Chickens in India

“…In addition to their wide range of efflux substrates, these multiple drug resistance pumps also facilitate bacterial adaptation to different niches (47). The presence of AcrAB-TolC and CmeABC RND efflux pumps suggests H. pullorum's extraordinary defense against a wide range of host-derived substrates, and these pumps could also play an important role in bacterial adherence to and invasion of host epithelial cells, as observed in Salmonella Typhimurium (48) and C. jejuni (49) infections, respectively.…”

Vitamin K 3 Induces the Expression of the Stenotrophomonas maltophilia SmeVWX Multidrug Efflux Pump

“…However, transient higher expression levels can be reached due to some particular physiological situations, as a response to stress or in the presence of effectors, including host-produced anti-infective molecules, such as bile, cationic peptides, or fatty acids (16)(17)(18), as well as agents used for therapeutic purposes, some of which might be relevant in the course of an infection (19). Knowing these effectors can be useful for understanding the role of these MDR efflux pumps besides resistance to antibiotics, as well as for predicting situations of transient antibiotic resistance that may occur in vivo (20).…”

“…RND efflux pump substrates are very diverse and include antibiotics, biocides, bile salts, detergents, aromatic hydrocarbons, homoserine lactones, and dyes (21); however, the number of known inducers that can trigger their expression is lower in comparison (20). In the present study, we have carried out a screening in order to identify potential effectors of the S. maltophilia RND efflux pump SmeVWX, using a yellow fluorescent protein (YFP)-based sensor.…”

Why Non-Specific Adaptation Mechanisms Inevitably Lead to the Emergence of Bacterial Strains Multiresistant to Antibiotics

“…These mechanisms may result in a degree of total or partial resistance, which is related to the specific nature of the resistance mechanism, for example the resistance that is developed as a result of the chemical modification of an antibiotic is total, since it inhibits the potential interactions with the target in the bacteria physiology, However, other resistance mechanisms confers partial resistance, but for this, the process involves decrease by different procedures the interactions between target and the antibiotic. One of these mechanisms has already been reported as one of particular importance to explain the emergence of superbugs' strains is the cellular efflux [6]. The main feature to adaptive purposes is that they are inherently nonspecific and therefore are promiscuous, understanding that they are able to interact with very different nature elements [7].…”