Beyond killing: Can we find new ways to manage infection?

Abstract

The antibiotic pipeline is running dry and infectious disease remains a major threat to public health. An efficient strategy to stay ahead of rapidly adapting pathogens should include approaches that replace, complement or enhance the effect of both current and novel antimicrobial compounds. In recent years, a number of innovative approaches to manage disease without the aid of traditional antibiotics and without eliminating the pathogens directly have emerged. These include disabling pathogen virulence-factors, increasing host tissue damage control or altering the microbiota to provide colonization resistance, immune resistance or disease tolerance against pathogens. We discuss the therapeutic potential of these approaches and examine their possible consequences for pathogen evolution. To guarantee a longer half-life of these alternatives to directly killing pathogens, and to gain a full understanding of their population-level consequences, we encourage future work to incorporate evolutionary perspectives into the development of these treatments.

Keywords: anti-virulence drugs; damage limitation; disease tolerance; evolution; infection; microbiota.

Figure 1.

Examples of anti-virulence approaches. (A) In a classical infection, bacteria adhere to host tissue using their flagella and pilli. They then secrete quorum-sensing molecules (red dots) to communicate with nearby cells in order to coordinate the secretion of harmful virulence factors (green pentagons), such as toxins and tissue-degrading enzymes. (B) A potent anti-virulence approach is to prevent bacterial adhesion by the administration of hydrophilic compounds (purple layer) [15]. (C) Interference with bacterial communication, called quorum-quenching has been proposed as another efficient way to control bacterial infections. Numerous drugs (yellow half-circles) have been shown to either quench the bacterial signals outside the cell or to directly stall signal production within cells [26], (D) Approaches have also been developed to target the damaging virulence factors (e.g. siderophores, toxins) directly by either suppressing their synthesis or by inhibiting their actions once secreted [12]

Figure 2.

When comparing the ability of two different groups of hosts to limit damage during infection (e.g. a group with or without a damage control therapy), a common approach is to analyse how host health changes with increasing infection loads for each of the groups of interest. As pathogen loads increase during infection, hosts will lose health, going from a state of no symptoms to illness, and in extreme cases even death. In its simplest form, this relationship may be linear [30, 37], and host groups showing steep negative slopes for this reaction norm suffer a loss in health with increasing loads, while hosts with flat reaction norms are able to maintain health even as pathogen loads increase, and are therefore relatively tolerant. A potentially more realistic outcome is a non-linear relationship between host health and pathogen load. Hosts with more efficient damage prevention or repair mechanisms are able to maintain a higher level of health during infection (blue line) by affecting the sensitivity, slope or severity of the dose-response curve. The aim of therapies that promote tissue damage control is to flatten these relationships (by increasing the period before health plunges and/or lowering the slope)