Interactions among strategies associated with bacterial infection: pathogenicity, epidemicity, and antibiotic resistance

Abstract

Infections have been the major cause of disease throughout the history of human populations. With the introduction of antibiotics, it was thought that this problem should disappear. However, bacteria have been able to evolve to become antibiotic resistant. Nowadays, a proficient pathogen must be virulent, epidemic, and resistant to antibiotics. Analysis of the interplay among these features of bacterial populations is needed to predict the future of infectious diseases. In this regard, we have reviewed the genetic linkage of antibiotic resistance and bacterial virulence in the same genetic determinants as well as the cross talk between antibiotic resistance and virulence regulatory circuits with the aim of understanding the effect of acquisition of resistance on bacterial virulence. We also discuss the possibility that antibiotic resistance and bacterial virulence might prevail as linked phenotypes in the future. The novel situation brought about by the worldwide use of antibiotics is undoubtedly changing bacterial populations. These changes might alter the properties of not only bacterial pathogens, but also the normal host microbiota. The evolutionary consequences of the release of antibiotics into the environment are largely unknown, but most probably restoration of the microbiota from the preantibiotic era is beyond our current abilities.

FIG. 1.

Infection and antibiotic treatment are both stringent growing conditions. Several bacteria are able to grow at the temperature and oxygen tension of and using the nutrients present in the human body. However, only some are able to produce infection; this is shownin panel A. Several bacterial species (ovals are pathogens, circles are environmental ones) coexist outside the host. Some species are able to displace the commensal flora, traverse through different epithelia, resist the action of macrophages, antibodies, defensins (with squares), and all the anti-infectious mechanisms of the human body, to finally reach the target cells where the disease is produced. At any of these sequential bottlenecks, only some bacteria are selected, and their population is further amplified, so that, from the high variability of bacteria that could potentially produce the disease, only some are really pathogenic. In panel B, the same situation is analyzed but under antibiotic treatment (spheres). In this case, only a small proportion of the cells belonging to the infectious species (the antibiotic-resistant ones; blue ovals with a red line) are able to produce infection, so that the antibiotic-treated host is a more stringent ecosystem for the growth of bacteria. However, in the case of a debilitated person (panel C), the situation is somewhat different. In these patients, the indigenous microflora might be removed because of antibiotic use, the epithelial integrity may be impaired (intubated patients), the immune system can be abolished (immunocompromised patients), and even the target cells can change. Under these circumstances, some environmental species can produce infection (opportunistic pathogens), because growth conditions are less stringent. However, at least in the developed world, those patients are usually under heavy antibiotic treatment, frequently with a combination of antibiotics (golden and blue spheres), so that only those species with an intrinsically antibiotic-resistant phenotype can produce the infection. Under these circumstances, the main selective force is antibiotics, so that antibiotic treatment becomes a risk factor for some pathogens.

FIG. 2.

Structure of an integron. Integrons are site-specific recombination elements that mediate the acquisition and spread of genes among bacterial populations. Integrons are formed by an integrase gene followed by one primary att recombination site (dark grey box) and several cassettes, each including one gene and one 59-bp recombination site (white square). The transcription of the system is controlled by a strong promoter located upstream of the integron. This structure favors the arrangement of genes in tandem, which are transferred as single elements among bacterial populations.

FIG. 3.

Epidemic bacteria can easily acquire an antibiotic-resistant phenotype. An epidemic bacterial strain (green) spreading between hosts (each individual blue square) increases its population size, facilitating the emergence of antibiotic-resistant mutations (yellow arrow) and the acquisition of resistance genes by horizontal transfer (brown arrow). Acquisition of resistance is immediately amplified by the epidemicity of the strain, even in the absence of antibiotic selection (resistant variants, yellow and brown). Interactions between different mechanisms of resistance may occur, eventually leading to multiresistance (red). If antibiotics are almost ubiquitously present in the hosts, as in an intensive care unit (black squares), the spread of the resistant bacteria is favored.

FIG. 4.

Colonization space of opportunistic pathogens. Colonization space can be defined as the combination of the different physicochemical parameters (including the space) in which an organism can survive. In this regard, stringent growth conditions (for instance, absence of oxygen) reduce the ecological space. As discussed, conditions for infection are quite stringent, so that only a few bacteria can colonize the host's ecological space (dark gray square) compared to bacteria that colonize the environment and, eventually, the dead host (lightly shaded square). In the case of the sick host, however, stringency for colonization is lower, so that some environmental bacteria can now colonize this larger ecological space (intermediately shaded square in panels b and c). These bacteria with an environmental origin are opportunistic pathogens. Once infected with these bacteria, the host is usually treated with antibiotics. Again, antibiotic treatment restricts the ecological space so that only antibiotic-resistant bacteria can grow under these conditions (oval in C). In all cases, small ovals indicate human-associated bacteria and small circles indicate environmental bacteria. White, antibiotic-susceptible bacteria; black, antibiotic-resistant bacteria.

FIG. 5.

Infectious bacteria under risk of antibiotic treatment. As stated in the text, in some cases infections are extremely acute (black line), so that the host is damaged (and even killed) before an antibiotic treatment is implemented. Other infections present no symptoms and have subclinical manifestations, so that they are not treated even if they occur for long periods of time (light gray line). Only infectious bacteria that produce clinically relevant symptoms and are present long enough to be treated (dark gray line) are under antibiotic selective pressure.