Writer: Chengzu Maxwell Xiang

There was once a time when a scratch or a bad apple could suddenly cut your life short. Those days now seem far behind us, some old story that parents tell their children to get them to take their medicine when they whine. But we forget that not even 100 years ago, 10% of all babies did not live to the age of one, and 25% did not see their fifth birthday. Yet with the onset of antibiotics, humanity now had a superweapon against the invisible terrors that had haunted us since the dawn of civilization. In the 1940s, the infant mortality rate (in Canada) had dropped to 47 babies for every one thousand live births. The mortality rate for sepsis and meningitis dropped from 90% to 10%, the average life expectancy went from 47 to 78, and the elderly went from 4% of the American population to 9%. This happened within 50 years of the invention of antibiotics, and with such marvelous changes to our society, we have lost our respect for antibiotics.  

The history of antibiotics began with the observation of antibacterial chemicals at work. Paul Ehrlich observed how certain chemical dyes colored some bacterial cells but not others, concluding that it was possible to create substances that could kill certain bacteria without harming other cells. In 1909, Ehrlich discovered that a chemical called arsphenamine was an effective treatment for syphilis. Ehrlich referred to his discovery as ‘chemotherapy’, using chemicals to treat disease. The word ‘antibiotic’ would not be used until 1941 by Selman Waksman, who discovered over 20 antibiotics during his lifetime. Alexander Fleming discovered penicillin after a holiday in Suffolk in 1928, when he noticed a fungus, Penicillin notatum, had contaminated an uncovered culture plate of Staphylococcus bacteria. Fleming observed that the fungus created bacteria-free zones wherever it grew on the plate, so he isolated and grew the mold in a pure culture. He discovered that the soluble substance produced by P. notatum was extremely effective at preventing Staphylococcus growth even when diluted 800 times, and was less toxic than the disinfectants used at the time. Fleming purified the active agent and named it penicilin.  

The discovery of penicillin, along with reports of the production of antimicrobial compounds by microorganisms, led Selman Waksman to start a systematic study of microbes as producers of antimicrobial compounds in the late 1930s. Waksman defined an antibiotic as ‘a compound made by a microbe to destroy other microbes’ and was instrumental in identifying Actinomycetes as a prolific producers of antimicrobial compounds, leading to the discovery of many antibiotics, including neomycin and streptomycin, which was the first active agent against tuberculosis. Waksman’s work also identified Streptomyces as producers of secondary metabolites, which are compounds not required for the normal growth, development, and reproduction of an organism in the laboratory. Many of these secondary metabolites are active against bacteria, fungi, viruses, nematodes, and insects. They have also been developed as anti-cancer and immunosuppressant drugs.  

Waksman’s work initiated the Golden Age of antibiotics from the 1940s to the 1960s. Many of the antibiotics discovered during this time are still in clinical use, but their effectiveness has declined with the rise of antibiotic-resistant bacteria.  Additionally, the rapid and relatively easy discovery of multiple classes of secondary metabolite (NP) antibiotics during a relatively short period of time has led to the overuse and dependence on these drugs. Combined with the lack of new antibiotics from the 1970s onward, this leads to the current situation with few new antibiotics in clinical trials. In fact, the majority of antibiotics in clinical trials today are derivatives of known classes of NP or synthetic antibiotics. The lack of new antibiotic discoveries also coincides with decline in the discovery of new NP families, and the persistent rediscovery of known compounds in screening campaigns using microbial, and predominantly actinomycete, fermentation extracts. This has partially contributed to the belief that all easily discovered NPs had been found, resulting in many major pharmaceutical and agrochemical companies shutting down their NP research departments. However, new antibiotic-producing strains have been recently discovered in under-explored environments, and combined with new tools for genome mining, the NP discovery field is making a comeback. 

Even with the possible return of the Golden Age of antibiotics, it is impossible to ignore the growing risk of antibiotic-resistant microbes. Antimicrobial medicines are the cornerstone of modern medicine. Antimicrobial Resistance (AMR) has significant impacts on our ability to treat common infections and perform life-saving procedures including cancer chemotherapy, caesarean section, hip replacements, organ transplants, and other surgeries. AMR also threatens the health of animals and plants, reduces productivity in farms, and impacts food security around the world. AMR costs the health system significant amounts of money for more expensive and intensive care and affects patients and caregivers through prolonged hospital stays.  

AMR is a problem for all countries. Its spread does not recognize borders. A lack of clean water, poor sanitation and hygiene, inadequate infection and disease control in homes, healthcare facilities and farms, little access to quality and affordable vaccines, diagnostics and medicines, are all reasons people living in low-resource settings and vulnerable populations are especially impacted by both the drivers and consequences of AMR. 

Antibiotic resistance results from natural resistance in certain types of bacteria, genetic mutations, and selective pressure from antibiotic use. Many socioeconomic and behavioral factors, especially in developing countries, accelerate the selection for resistant bacteria. Some of these factors include misuse of antibiotics by health professionals, inappropriate antibiotic use by unskilled practitioners, poor quality medicines, dissemination of resistant organism through overcrowded and unhygienic conditions, lack of resources to implement strategies against antibiotic resistances, and a lack of political concern. The rate at which antibiotic resistance is outpacing the discovery of new antibiotics is a cause for great concern, as there are very limited treatment options for multi-drug resistant pathogens.  

Microorganisms gain resistance to antibiotics though many different defense methods such as: restricting access of the antibiotic by changing the entryway or limiting number of entryways, removing the antibiotics using pumps in the cell wall, breaking down or changing the antibiotic with enzymes, or even developing new cell processes that avoid using the antibiotic’s target. 

Bacterial resistance, for example, can be either intrinsic to an organism or acquired through genetic change, often via spontaneous mutation or horizontal gene transfer. Bacteria may also transiently display resistance (adaptive resistance) in response to external stimuli. Some bacterial species possess inherent structural or biochemical traits that confer natural resistance to certain drugs, such as lacking certain binding sites or a specific structure that the antibiotic targets. 

Acquired resistance develops through chromosomal mutations or by acquiring resistance genes from other organisms. Resistance genes can spread between bacteria through transformation, taking up foreign DNA from their surroundings, often from dead bacteria, transduction, caused by bacteriophages that package chromosomal DNA from host cells, or conjugation, a natural, contact-dependent mechanism. 

Adaptive resistance is when bacteria develop transient resistance in response to environmental pressures, such as the expression of efflux pumps or the formation of biofilms. The resistance appears to dissipate upon the removal of the external stressor. Some methods used include enzymatic inactivation, producing enzymes that deactivate antibiotics, target side modification, altering the antibiotic binding sites, reduced permeability and efflux, restricting intracellular drug levels by decreasing the permeability of the outer membrane, or by actively pumping out drugs via efflux transporters, metabolic bypass, evading an antibiotic’s effect by bypassing the targeted metabolic pathway, substrate production, increasing the amount of substrates that compete with antibiotics for binding sites, biofilm formation, embedding themselves in a protective extracellular matrix that limits antibiotic penetration, and within biofilms, bacteria can enter dormant states or activate stress responses, making them less susceptible to antibiotics. 

 The rising rates of AMR poses a significant threat, as 76 countries report a median of 42% for third-generation cephalosporin-resistant E. coli, and 35% for methicillin-resistant Staphylococcus aureus. E. coli strains produce Extended-Spectrum Beta-Lactamase (ESBL) or AmpC enzymes which destroy the antibiotic, while Staphylococcus aureus gains immunity through a foreign gene called mecA, which codes for an altered protein called PBP2a. This altered protein has a completely different shape than PBP, which is normally used to build Staphylococcus aureus cell walls. This altered shape stops methicillin from binding to or inhibiting it, allowing the bacterium to build its cell wall and reproduce in the presence of the antibiotic. 

Fungal infections are already difficult to treat due to similarities between fungal cells and human one, making it difficult for medication to target the fungus without causing significant side-effects in the host, making the spread of multi-drug  resistant Candida auris, an invasive fungal infection, particularly concerning.  

HIV drug resistance (HIVDR) is caused by changes in the HIV genome that affects the ability of antiretroviral (ARV) drugs to block the replication of the virus. HIVDR can be transmitted at the time of infection or through inadequate adherence to treatment procedures. HIVDR leads to increased HIV infections and mortality rates. 

Tuberculosis and malaria are both growing threats towards underdeveloped countries, as the most effective treatments become less effective, making them harder to control in already poor conditions. Multidrug-resistant tuberculosis (MDR-TB) is a form of TB caused by bacteria that do not respond to isoniazid and rifampicin, the two most effective first-line TB drugs. MDR-TB is treatable and curable, but only with second-line drugs, which are both expensive and toxic, and risks further drug resistance. TB cases that do not respond to the most effective second-line TB drugs leave patients with very limited treatment options. MDR-TB is a threat to public health and health security. Only 2 in 5 people with drug resistant TB accessed treatment in 2022. 

The growing rates of artemisinin resistance poses a major threat to developing countries, as artemisinin-based compounds (ACTs) are the recommended first-line treatment for uncomplicated Plasmodium falciparum cases, and are used by most malaria endemic countries. The emergence of partial resistance to artemisinin and/or partner drugs in ACTs make selecting the right treatment more difficult, and requires close monitoring to prevent further development. In the Greater Mekong Subregion (Southeast Asia), partial resistance to artemisinin or a partner drug has been confirmed in several countries since 2001, and in the WHO Eastern Mediterranean Region, resistance to a partner drug, sulfadoxine-pyrimethamine, has led to treatment failure in several countries requiring a change to another ACT. In Africa, mutations linked to artemisinin partial resistance have been found in multiple countries. ACTs that have been tested remain effective, but further spread of resistance could be a major public health challenge, and improved surveillance remains vital. 

The rise of AMR has not been treated with the seriousness it deserves, thanks to its slow and invisible nature, combined with poor financial incentives for new drug development, agricultural overuse of antibiotics, and a lack of rapid point-of-care diagnostics, forcing doctors to prescribe broad-spectrum antibiotics far too frequently. Only in recent years have global governments begun treating this problem seriously. 

The Program/Committee on the Global Action Plan on Antimicrobial Resistance by the World Health Organization (WHO) was launched with the primary aim of stemming the tide of antimicrobial resistance. The five strategic goals of the plan include: to improve awareness and understanding of AMR; to strengthen surveillance and research; to reduce the incidence of infection; to optimize the use of antimicrobial medicines and to ensure sustainable investment in countering AMR. 

AMR is a deadly and growing threat to modern medicine, and there is a desperate need for the education of the patients and general community on the appropriate use of antibiotics, importance of infection preventive measures, and proper and informed health care seeking behavior. People must be educated on alternatives to antibiotics for symptom relief, and the importance of avoiding self-medication. Continued medical education for prescribers and dispensers on the rational use of antibiotics, discouraging financial incentives for irresponsible prescriptions, the separation of the medical industry from private investment, and a global coordinated effort are all required steps to fight the growth of AMR. 

References: 

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CDC. 2025. “About Antimicrobial Resistance.” Antimicrobial Resistance. Centers for Disease Control and Prevention. January 31, 2025. https://www.cdc.gov/antimicrobial-resistance/about/index.html. 

Clardy, Jon, Michael A. Fischbach, and Cameron R. Currie. 2009. “The Natural History of Antibiotics.” Current Biology 19 (11): R437–41. https://doi.org/10.1016/j.cub.2009.04.001. 

Habboush, Yacob, and Nilmarie Guzman. 2023. “Antibiotic Resistance.” National Library of Medicine. StatPearls Publishing. June 20, 2023. https://www.ncbi.nlm.nih.gov/books/NBK513277/. 

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Jun‐ichi Wachino. 2025. “Horizontal Gene Transfer Systems for Spread of Antibiotic Resistance in Gram‐Negative Bacteria.” Microbiology and Immunology, May. https://doi.org/10.1111/1348-0421.13222. 

Microbiology Society. 2020. “The History of Antibiotics.” Microbiologysociety.org. 2020. https://microbiologysociety.org/why-microbiology-matters/knocking-out-antimicrobial-resistance/amr-explained/the-history-of-antibiotics.html. World Health Organization. 2023. “Antimicrobial Resistance.” World Health Organization. November 21, 2023. https://www.who.int/news-room/fact-sheets/detail/antimicrobial-resistance