The intrinsic resistome of bacterial pathogens

Abstract

Intrinsically resistant bacteria have emerged as a relevant health problem in the last years. Those bacterial species, several of them with an environmental origin, present naturally low-level susceptibility to several drugs. It has been proposed that intrinsic resistance is mainly the consequence of the impermeability of cellular envelopes, the activity of multidrug efflux pumps or the lack of appropriate targets for a given family of drugs. However, recently published articles indicate that the characteristic phenotype of susceptibility to antibiotics of a given bacterial species depends on the concerted activity of several elements, what has been named as intrinsic resistome. These determinants comprise not just classical resistance genes. Other elements, several of them involved in basic bacterial metabolic processes, are of relevance for the intrinsic resistance of bacterial pathogens. In the present review we analyze recent publications on the intrinsic resistomes of Escherichia coli and Pseudomonas aeruginosa. We present as well information on the role that global regulators of bacterial metabolism, as Crc from P. aeruginosa, may have on modulating bacterial susceptibility to antibiotics. Finally, we discuss the possibility of searching inhibitors of the intrinsic resistome in the aim of improving the activity of drugs currently in use for clinical practice.

Keywords: MDR efflux pump; biofilms; intrinsic resistance; persistence; phenotypic resistance; swarming.

FIGURE 1

The different elements in bacterial resistance to antibiotics. All bacteria have a repertoire of elements that contribute to their characteristic phenotype of susceptibility to antibiotics, what has been dubbed as intrinsic resistome. Some of the elements of this resistome are classical resistance elements, as antibiotic-inactivating enzymes, whereas others belong to all functional categories. The mutation of some of these elements makes bacteria more susceptible to antibiotics, whereas for some others increased resistance is acquired. Nevertheless, acquisition of a phenotype of increased resistance to antibiotics not always implies a genetic change, either because of mutation or as the consequence of the acquisition of a resistance gene by horizontal gene transfer. Phenotypic, non-inheritable resistance can be achieved by different processes that include, among others, growth in biofilms, swarming adaptation, and development of persistence.