In the first half of the 20th century, tuberculosis was a leading cause of death and effective treatments were scarce. Waksman systematically examined chemicals made by soil actinomycetes and isolated streptomycin in 1943. This drug was the first antibiotic that could kill Mycobacterium tuberculosis and worked against pathogens that penicillin could not defeat. Clinical trials showed dramatic improvements in symptoms and survival, marking a breakthrough for humanity. Because resistant bacteria soon appeared when the drug was used alone, it is now routinely combined with other medicines. Waksman’s work launched a wave of antibiotic hunting from soil microbes that still guides modern drug discovery.

Streptomycin is an aminoglycoside antibiotic produced by Streptomyces griseus; it binds to the 30S ribosomal subunit of bacteria and blocks protein synthesis. When it was discovered, penicillin’s activity was largely confined to Gram-positive bacteria, so researchers were searching for agents active against Gram-negative organisms and tuberculosis. Waksman and his students screened thousands of actinomycete cultures and identified one that inhibited tuberculosis bacilli in vitro. Animal studies and early clinical trials beginning in 1944 confirmed both efficacy and acceptable safety. The success of streptomycin stimulated the development of follow-up drugs such as isoniazid and rifampicin and pushed tuberculosis therapy toward multidrug regimens. The emergence of resistance highlighted new challenges for antimicrobial research and underscored the importance of natural-product chemistry.

Waksman implemented systematic bioassays of actinomycete metabolites and purified streptomycin by low-temperature column chromatography. The compound’s aminoglycoside scaffold, composed of deoxystreptamine linked to methylated pentoses, was later confirmed by NMR and X-ray crystallography. It binds the bacterial 30S ribosome and induces codon-misreading, producing a bactericidal effect. Minimum inhibitory concentrations of 0.8–3.2 µg/mL were reported against M. tuberculosis, and high pulmonary tissue distribution was observed in vivo. A 1947 clinical trial reduced mortality from 49 % to 8 %, demonstrating significant therapeutic benefit. However, rpsL and rrs mutations generated rapid resistance, exposing the limitations of monotherapy. These insights prompted combination regimens with PAS and isoniazid, shaping subsequent anti-TB drug development. Streptomycin also became a chemical probe in ribosome research, advancing studies of translational fidelity. Waksman’s soil-screening protocol later guided the discoveries of chloramphenicol and erythromycin, establishing natural-product drug discovery as a discipline.