Approaches to the development of new antituberculosis drugs.

In the last two decades, no new major antituberculosis drug has been developed. Although dramatic improvements in chemotherapy for tuberculosis have been achieved through careful studies of drug regimens, there is still a need for new agents that are highly active. The antimycobacterial drugs used at present in therapy for tuberculosis were obtained by either blind screening or chemical modification of active compounds, with tentative optimization of chemotherapeutic properties. Other approaches based on knowledge of the biochemistry of the mycobacterial cell should be tried. Certain constituents of the cell, such as mycolic acids, arabinogalactan, peptidoglycan, and mycobactins, may represent specific targets for new antituberculosis drugs. Products interfering with the biosynthesis of these mycobacterial constituents can be expected to show specific activity against these microorganisms, with no effect on the normal bacterial flora.

History of the development of rifampin.

Rifampin was developed in the Dow-Lepetit Research Laboratories (Milan, Italy) as part of an extensive program of chemical modification of the rifamycins, the natural metabolites of Nocardia mediterranei. One peculiar fact was that all of the studies leading to highly active derivatives were performed on a molecule (rifamycin B) that was itself practically inactive. The first chemical modifications led to the discovery of rifamycin SV, which was introduced in some countries for the parenteral and topical treatment of infections due to gram-positive bacteria and infections of the biliary tract. Systematic structural modifications of most of the functional groups of the rifamycin molecule were performed with the objective of finding a derivative that was active when administered orally. The understanding of structure-activity relations in the rifamycins led to the synthesis of several hydrazones of 3-formylrifamycin SV. Among them, the hydrazone with N-amino-N'-methylpiperazine (rifampin) was the most active in the oral treatment of infections in animals and, after successful clinical trials, was introduced into therapeutic use in 1968. In the intervening years, a large number of clinical and biologic studies have confirmed the important role of rifampin in therapy for tuberculosis and other selected infectious diseases.

Trends in the research on antimicrobial agents.

The pharmacotherapy of microbial diseases has achieved brilliant success in the last 40 years, but it still deserves a great research interest. In fact, microbial infections remain the major cause of morbidity, with a definite incidence in mortality. Several dozen antimicrobial agents have been introduced in the therapy of infectious diseases. An active area of research concerns deepening knowledge of chemotherapeutic activity in various pathological conditions, mechanism of action, development of resistance, kinetics, and untoward effects of the available drugs in order to achieve the best utilization. Many researches are also directed at identifying the proper use of combinations of antimicrobials to define synergistic effect or inhibition of resistant strain selection. Finally there are continuous research efforts toward the development of new agents to overcome the drawbacks of the available ones. This problem is approached mainly in two ways, either by modification of the present antimicrobial drugs or by search for completely new entities through various screening sophistications. Examples of studies and results in the mentioned fields are reviewed.