## 1 Serendipitous Drug Discovery: Early Chemotherapy  
The first successful chemotherapy and cure of an infectious disease is indeed the discovery and design of the 'first line' therapy for the treatment of tuberculosis--the design and development of which was completed in the 1960s. Even today, this regimen is the therapy of choice for treating drug-sensitive tuberculosis (DSTB). The drugs in the first-line treatment for DSTB, isoniazid, rifampicin, pyrazinamide, and ethambutol became anti-TB drugs based on their activity on _Mycobacterium tuberculosis_ (MTB) cells in vitro, followed by testing in animal models and their rapid introduction into humans [1]. This progression was driven by the medical need, as no chemotherapy existed before these drugs were discovered.  
It is interesting to note that two biological observations and a hypothesis on potential 'chemical structures' that may interfere with the observed biological process were the first starting points of anti-TB drug discovery. Aspirin was shown to be a potent stimulator of the TB bacilli's 'oxygen consumption'; analogs of aspirin were then postulated to be inhibitors of this process. This led to the synthesis of a number of aspirin-like structures, of which para-aminosalicylic acid (PAS) became a successful anti-TB drug [1; 2; 3]. The second observation was that niacin helped in the recovery of guinea pigs infected with MTB, as well as the observation that niacin helped in faster recovery of TB patients, raising the possibility that niacin was acting as a 'vitamin' [4; 5]. Chemical synthesis focused on making derivatives of niacin led to the design of three anti-TB drugs, namely isoniazid (Inh), pyrazinamide (Pza) and ethionamide (Eth) [6]. Two of these are even today the most potent drugs for the treatment of TB. This early period of chemotherapy also included extensive search for natural products with antibacterial activity; Rifamycin and Streptomycin were natural products that showed potent activity against MTB cells and were also introduced into the treatment of TB.  
In 1979, [PERSON] observed that 10 to 12 drugs were available for the treatment of tuberculosis, which could be classified in terms of their effectiveness [7]. The choice of combinations was dictated by animal toxicity of the individual drugs and in human trials, which assessed time taken to the sputum negative state, cure as reflected by relapse rates, the emergence of resistant strains, and compliance. Once an effective combination had been proven, it became to be referred to as the 'Short Course Chemotherapy' and was adopted systematically all over the world [8]. This was the first successful conquering of an infectious disease. In about 20 years, TB patients went from complete helplessness to an effective cure achieved with drug treatment.  
The key learning from this pioneering era was as follows:  
1. In vitro MIC (Minimum Inhibitory Concentration) was insufficient to predict efficacy in humans. Requirement for a combination therapy of drugs.
2. The best regimen required six months of treatment to achieve cure.
3. Each of the drugs in the combination had a unique role to play in leading to the cure.  
The cure was defined as the lack of relapse.  
The last two points remain, to date, the biggest challenge in finding and developing novel combinations. The era of 1950 to 1980 had 10 drugs, of which the most efficacious combination of four drugs was identified through rapid testing in humans. In spite of more than two decades of sustained research into the biology of MTB, the traits of a new drug that could contribute to both the 'cure' and the shortening of therapy are still unknown.