First drugs
Rifamycins were first isolated in 1957 from a fermentation culture of Streptomyces mediterranei at the laboratory of Gruppo Lepetit SpA in Milan by two scientist named Piero Sensi and Maria Teresa Timbal, working with the Israeli scientist Pinhas Margalith. Initially, a family  of closely related antibiotics was discovered referred to as  Rifamycin A, B, C, D, E. The only component of this mixture sufficiently stable to isolate in a pure form was Rifamycin B, which unfortunately was poorly active. However, further studies showed that while Rifamycin B was essentially inactive, it was spontaneously oxidized and hydrolyzed in aqueous solutions to yield the highly active Rifamycin S. Simple reduction of Rifamycin S yielded the hydroquinone form called Rifamycin SV, which became the first member of this class to enter clinical use as an intravenous antibiotic. Further chemical modification of Rifamycin SV yielded an improved analog Rifamide, which was also introduced into clinical practice, but was similarly limited to intravenous use. After an extensive modification program, Rifampin was eventually produced, which is orally available and has become a mainstay of Tuberculosis therapy

Lepetit filed for patent protection of Rifamycin B in the UK in August 1958, and in the US in March 1959. The British patent GB921045 was granted in March 1963, and U.S. Patent 3,150,046 was granted in September 1964. The drug is widely regarded as having helped conquer the issue of drug-resistant tuberculosis in the 1960s. Clinical trials
Rifamycins have been used for the treatment of many diseases, the most important one being HIV-related tuberculosis.
A systematic review of clinical trials on alternative regimens for prevention of active tuberculosis in HIV-negative individuals with latent TB found that a weekly, directly observed regimen of rifapentine with isoniazid for three months was as effective as a daily, self-administered regimen of isoniazid for nine months. But the rifapentine-isoniazid regimen had higher rates of treatment completion and lower rates of hepatotoxicity. However, the rate of treatment-limiting adverse events was higher in the rifapentine-isoniazid regimen.The rifamycins have  a unique mechanism of action, selectively inhibiting bacterial DNA-dependent RNA polymerase, and show no cross-resistance with other antibiotics in clinical use. However, despite their activity against bacteria resistant to other antibiotics, the rifamycins themselves suffer from a rather high frequency of resistance. Because of this, Rifampin  and other rifamycins are typically  used in  combination with other antibacterial drugs. This is routinely practiced in TB therapy and serves to prevent the formation of mutants that are resistant to any of the drugs in the combination. Rifampin rapidly kills fast-dividing bacilli strains as well as "persisters" cells, which remain biologically inactive for long periods of time that allow them to evade antibiotic activity. In addition, rifabutin and rifapentine have both been used against tuberculosis acquired in HIV-positive patients. Although Tuberculosis therapy remains the most important use of Rifampin, an increasing  problem with serious Multiple Drug Resistant bacterial infections has led to some  use of antibiotic combinations containing Rifampin to treat them.