Antimicrobial resistance has ancient roots, but its public health threat is growing now

Antimicrobial resistance (AMR) is now killing more than a million people worldwide each year, making it one of the most urgent global health threats facing human and veterinary medicine. However, the roots of the crisis stretch back long before modern antibiotics entered medicine, according to a review published in the journal Antibiotics.

The study, titled The Silent Pandemic: Antimicrobial Resistance, a Global Threat with Ancient Roots, traces the early recognition of antimicrobial resistance from pre-antibiotic chemotherapeutic agents such as Salvarsan to the first documented failures of sulfonamides and penicillin, arguing that resistance is not a modern surprise but a biological process repeatedly exposed by medical history.

Resistance was visible before Penicillin

The review challenges the narrative that AMR emerged only after the widespread use of antibiotics in the mid-20th century. Instead, it shows that scientists had observed microbial adaptation decades earlier. One of the earliest examples involved Salvarsan, also known as arsphenamine or compound 606, a synthetic arsenic-based drug developed by Paul Ehrlich for syphilis and African trypanosomiasis. Salvarsan became a major medical breakthrough because it was more effective than older mercury-based treatments for syphilis. Its improved form, Neosalvarsan, was introduced in 1913 and remained an important treatment until antibiotics arrived.

However, resistance concerns emerged early. Ehrlich had already observed between 1907 and 1909 that Trypanosoma parasites could develop resistance after repeated exposure to sub-lethal doses of arsenic compounds. In 1924, a clinical case of resistance to Salvarsan was recorded in a patient with syphilis. The review identifies this as an early warning that microorganisms could adapt to antimicrobial pressure.

Salvarsan was not an antibiotic in the modern sense, but the resistance pattern foreshadowed what would later unfold with sulfonamides and penicillin. Prolonged or interrupted treatment placed selective pressure on microbes, allowing resistant organisms to survive and spread.

The review also discusses early research on drug inactivation. In 1919, S.M. Neuschlosz reported that Paramecium caudatum could acquire resistance to quinine and dyes by destroying toxic agents through enzymatic detoxification. The finding helped establish a key principle in modern resistance science: organisms may neutralize antimicrobial compounds, not merely tolerate them.

These early observations point to a larger biological truth. Microbial resistance did not begin with the misuse of modern antibiotics. The ability to survive chemical attack is an ancient and adaptive feature of microbial life. Human use of antimicrobial drugs accelerated the process by adding powerful selective pressure.

Sulfonamides and Penicillin turned warning signs into a medical crisis

The introduction of sulfonamides in the 1930s transformed infectious disease treatment. Prontosil, developed through research at Bayer and later understood to work through sulfanilamide, helped treat infections including pneumonia, sepsis and puerperal infection before penicillin became widely available.

The review describes sulfonamides as a medical revolution, but also as an early lesson in how quickly resistance can follow therapeutic success. As sulfonamides were used widely, including prophylactically during the Second World War, resistant microorganisms appeared within a few years.

Resistance to sulfonamides was documented as early as 1937 in cases of gonorrhea treated at Johns Hopkins Hospital in Baltimore. By 1944, treatment failure rates had risen above 30 percent. By the late 1940s, more than 90 percent of Neisseria gonorrhoeae samples taken from infected patients and grown in laboratory conditions were resistant to sulfonamides.

These developments alarmed physicians, who warned against indiscriminate use and argued that sulfonamides should be available only under medical supervision. The concern mirrored today’s antimicrobial stewardship debates: when drugs are overused, under-dosed or used without careful targeting, resistance accelerates.

Penicillin, often remembered as the great turning point in modern medicine, quickly produced similar warnings. Although penicillin became available for medical use in the United States in 1943, resistance mechanisms had already been identified. In 1940, Edward Abraham and Ernst Boris Chain detected a strain of Escherichia coli able to produce penicillinase, an enzyme that could destroy penicillin.

In 1942, Charles Henry Rammelkamp Jr. and Thelma Maxon documented resistance in some Staphylococcus aureus strains from hospitalized patients. Laboratory work also showed that Staphylococcus aureus could develop resistance when exposed to weak concentrations of penicillin over successive generations.

Alexander Fleming warned about that danger when he received the Nobel Prize in 1945. The review notes that Fleming clearly recognized the risk of under-dosing and uncontrolled access to penicillin, warning that exposure to non-lethal quantities could make microbes resistant. Within years, these concerns became reality. At London’s Hammersmith Hospital, bacteriologist Mary Barber documented the rise of penicillin-resistant Staphylococcus strains. Resistant strains were rare before 1944, but increased from 12.5 percent to 38 percent between 1946 and 1947. By 1948, the incidence had risen to 59 percent.

Barber’s work became key to early antibiotic-resistance awareness. She linked hospital spread to resistant strains, cross-infection and the role of healthcare workers as carriers. Her later work at St. Thomas Hospital showed that nursing staff could become nasal carriers of resistant bacteria after working in wards, adding urgency to infection-control practices.

The review presents Barber as a pioneer in the fight against antibiotic resistance. She argued for limiting antibiotic overuse and strengthening hospital hygiene. Her work helped establish a principle that remains central today: antibiotics alone cannot control infection if hospitals fail to prevent transmission.

A One Health response is needed as ancient resistance meets modern misuse

AMR is now driven by a complex mix of clinical, agricultural, veterinary, environmental and social factors. Inappropriate antimicrobial use in humans, animals and agriculture remains a major driver, but the problem is worsened by pollution, poor sanitation, weak hospital infrastructure, conflict zones, heavy metal contamination and limited access to clean water.

Resistant organisms and resistance genes can move across human, animal and environmental systems, making AMR a One Health challenge that requires a coordinated action across medicine, veterinary care, agriculture, food systems and environmental management.

Global surveillance has improved through the World Health Organization’s Global Antimicrobial Resistance and Use Surveillance System, which aims to strengthen standardized data collection and reporting. But the review stresses that surveillance alone is not enough. Effective control requires antimicrobial stewardship, improved diagnostics, stronger infection prevention, better hospital hygiene, responsible use in agriculture and new therapeutic options.

The review also highlights the limits of drug development. Since 2017, 13 new antibiotics targeting priority bacterial pathogens have received regulatory approval, and some are now included in the WHO Essential Medicines List. Yet resistance continues to evolve, including against newer agents. The antibiotic pipeline remains too limited to absorb the growing threat.

The review discusses the recent discovery of a 5,000-year-old bacterium preserved in ice in Romania’s Scăris,oara Ice Cave. The bacterium, a strain of Psychrobacter, was resistant to 10 antibiotics across eight classes and carried more than 100 resistance-linked genes. That finding reinforces that resistance traits existed long before modern medicine. The discovery also raises a future risk. As ancient ice melts, microorganisms and resistance genes preserved for thousands of years could enter modern environments.

Ancient microbes may also offer scientific opportunities, because some carry genes that could help identify new antimicrobial compounds or enzymes capable of blocking dangerous pathogens.

To sum up, AMR control must include rapid and molecular diagnostic testing so clinicians can target treatment more accurately and reduce unnecessary empirical antibiotic use. It must also include new antimicrobial molecules, optimized drug combinations and alternative therapeutic strategies.