Fresh approaches to anti-infective therapies

Abstract

If discovery of new antibiotics continues to falter while resistance to drugs in clinical use continues to spread, society's medicine chest will soon lack effective treatments for many infections. Heritable antibiotic resistance emerges in bacteria from nonheritable resistance, also called phenotypic tolerance. This widespread phenomenon is closely linked to nonproliferative states in ways that scientists are just beginning to understand. A deeper understanding of the mechanisms of phenotypic tolerance may reveal new drug targets in the infecting organisms. At the same time, researchers must investigate ways to target the host in order to influence host-pathogen relationships. Government must reform the regulatory process for approval of new antibiotics. The private sector, government, and academia must undertake multiple, organized, multidisciplinary, parallel efforts to improve the ways in which antibiotics are discovered, tested, approved, and conserved, or it will be difficult to sustain the modern practice of medicine.

Fig. 1. Diverse bacterial states

Many infectious diseases are complicated by the ability of bacterial pathogens to adopt diverse functional states that reduce the organisms’ susceptibility to antibiotics. This phenomenon is illustrated for tuberculosis, the leading cause of death from a single bacterial infection. VBNC, viable but nonculturable.

Fig. 2. Types of antibiotic resistance

Various bacterial states are associated with antibiotic resistance. See text for definitions and discussion.

Fig. 3. Intervening in infection

Standard approaches to the prevention or treatment of bacterial infection are pathogen-focused; either the host is immunized with an attenuated or killed pathogen or some of its components, to which the host's adaptive immune system responds, or the host is given drugs that inhibit bacterial synthesis of nucleic acids, proteins, cell walls, or folate. Researchers are beginning to explore new opportunities for the treatment of bacterial infections by targeting a wider range of pathways in the pathogen, as well as processes in the host that the pathogen relies on to cause disease. mAb, monoclonal antibody.