Clinical antimicrobial resistance was first reported four years before Alexander Fleming’s discovery of penicillin in 1928. The antimicrobial in question was known as Salvarsan (S. Silberstein Arch. Derm. Syph. 147, 116–130; 1924).
An antibiotic was originally defined as an agent that microorganisms produce to kill competing bacteria (S. A. Waksman Mycologia 39, 565–569; 1947). This has been extended to include synthetic drugs, including sulfonamides and quinolones. Salvarsan was one such drug, from a group of compounds known as arsphenamines. It was used to treat syphilis from 1910 until the 1940s, when penicillin took over because it was more readily available, safer and more effective.
Bacterial resistance to Salvarsan started to emerge about halfway through that period, despite the drug’s limited use by comparison with modern antibiotics. The 1924 paper was cited by several groups during the 1930s (see, for example, W. Beckh and G. V. Kulchar Arch. Derm. Syphilol. 40, 1–12; 1939), but has long since been forgotten.
Nature 562, 192 (2018)