Genetic Approaches to Facilitate Antibacterial Drug Development

Very few chemically novel agents have been approved for antibacterial chemotherapies during the last 50 yr.Yet new antibacterial drugs are needed to reduce the impact on global health of an increasing number of drug-resistant infections, including highly drugresistant forms of tuberculosis.This review discusses how genetic approaches can be used to study the mechanism of action of whole-cell screening hits and facilitate target-driven strategies for antimicrobial drug development.M any classes of antibiotics in clinical use to- day stem from the golden age of antibiotic discovery, which had its most productive period from 1940from to 1960from (Davies 2006;;Silver 2011).These drugs are one of the reasons why most bacterial infections can be cured with a few pills, generally without side effects, within a couple of weeks.It is thus easy to forget that bacterial infections have remained a major cause of preventable deaths in developing countries and continue to exert a profound impact on human health.The relative paucity of novel antibacterials discovered after 1960 coincided with the appearance and contributed to the spread of drug-resistant bacterial infections.When resistant to not only one, but multiple drugs, such infections threaten to erode a cornerstone of modern health care.Tuberculosis (TB) is a prime example of how treatment has succeeded in developed countries while meeting frequent failure in the developing nations.Treatment failure contributed to the reemergence of a thought-to-be-conquered dis-ease that now constitutes as a major public health threat.First-line treatment of TB consists of drugs originally identified during the golden age of antibiotic discovery.Together with social changes, these drugs contributed to a drastic reduction of TB cases in Europe and North America while continuing to kill millions in Africa and Asia.Drug-resistant Mycobacterium tuberculosis (Mtb) appeared shortly after the introduction of TB chemotherapy and evolved into extremely drug-resistant Mtb, which threatens the TB control programs worldwide.Therefore, the need for new therapies for treatment of this deadly disease remains unchanged since the preantibiotic era.This review discusses how genetic approaches can facilitate the development of drugs for such new therapies.