Ecological strategies to end the war on resistance
– by Kevin Blake and Gautam Dantas

The views and opinions expressed in this article are solely those of the original author(s) and do not necessarily represent those of GARDP, their donors and partners, or other collaborators and contributors. GARDP is not responsible for the content of external sites.

Military metaphors are pervasive in the language of antibiotics and resistance.¹ Bacterial pathogens are foreign invaders with whom we’re at war. To fight them we deploy antibiotic chemical weapons. Powerful antibiotics are big guns, narrow-spectrum antibiotics are silver bullets, and broad-spectrum antibiotics are nuclear bombs. We’re in a losing battle against antibiotic-resistant superbugs, and quickly running out of ammunition. Metaphors shape how you feel about an issue, and how you feel often determines the actions you take. Framing resistant bacteria as foes to be feared traps us within a fundamentally adversarial us-versus-them framework, where the only possible outcomes are their eradication—or ours.

Instead, a growing body of research is re-examining antibiotic resistance through the lens of microbial ecology and evolution. This work has revealed that bacterial resistance significantly predates human use of modern antibiotics, with resistance genes encoded by many benign environmental and commensal microbes often before they are detected in pathogens.² Unchecked antibiotic use can dramatically amplify these resistance reservoirs, select for their dissemination into pathogens, and engender significant negative side effects on human health.^3,4 Given the dwindling approval of new antibiotics,⁵ we must rethink the brute force approaches that attempt (futilely) to fight resistance by searching for the next bacteria-killing molecule. Instead, we should pursue complementary strategies that mitigate selection of antibiotic resistance by improving stewardship and developing novel chemotherapeutic, probiotic, and prebiotic strategies for suppressing bacterial virulence and supporting commensalism.

Like any good diplomatic strategy, the best approach to mitigate antibiotic resistance will be multi-pronged.

To contrast the military metaphors, we metaphorize these ecological approaches using the diplomatic terms of: disarmament, non-proliferation, and soft power. Strategies for targeted killing of pathogens must invariably remain part of our medical toolkit, but by pursuing these complementary strategies, we argue that we can better foster sustainable co-existence with our microbial co-habitants and tip the scales against pathogenesis.

Ancient origins

Most of our clinically important antibiotics were discovered as the natural products of soil-dwelling microbes, particularly the Actinomycetes. In 1973, Davies and Benveniste⁶ proposed that the origins of antibiotic resistance likely lie with these “producer” microbes as they would need elements to protect themselves from the antibiotics they produced. These elements, by definition, would be antibiotic resistance genes. The Producer Hypothesis postulates that, over time, nonproducers (including pathogens) have acquired these antibiotic resistance genes via horizontal gene transfer. With the evolution of antibiotic production estimated to have occurred hundreds of millions of years ago,⁷ antibiotic resistance must be just as old.

The ancient origin of resistance in soil-dwelling microbes explains several features of resistance which seem puzzling, even paradoxical, when viewed solely from a clinical perspective. First, it explains why soil-dwelling Actinomycetes encode resistance to more antibiotics than most clinical pathogens; seven or eight antibiotics on average and 15 at the upper end, including synthetic compounds recently approved for clinical use.⁸ It also explains why soils are an immense and diverse reservoir of previously unknown resistance genes not yet seen in pathogens, and how soil bacteria and human pathogens can encode identical resistance genes.⁹

Collateral damage

Zooming in on the subset of antibiotic-resistant bacteria associated with humans, an ecological perspective also reveals the unintended knock-on effects of antibiotics use. Pathogens are not the only microorganisms that make a home of the human body. Each human is colonized by an 500-1,000 species of bacteria, and the number of bacterial cells is roughly the same as the number of human cells.^10,11 These microbes form relatively stable ecosystems called microbiomes, which are just as diverse and complex as macroscopic ecosystems. The densest and most diverse human-associated microbiome is in the colon: the gut microbiome. A healthy gut microbiome is critical to human health and development, providing essential functions including nutrient processing, colonization resistance against pathogens, and immune system regulation.¹²

Antibiotics are developed with the intention of killing a select few pathogenic species; however, they do so by targeting conserved molecular features shared by thousands of species across broad branches of the tree of life (e.g., cell wall, ribosome, RNA polymerase). As a result, they can indiscriminately kill both “good” commensal species and “bad” pathogens when administered to humans. Taking antibiotics to treat a gut infection may kill the pathogen, but at the cost of potential significant collateral damage—another military metaphor—to commensal microbiota. Substantial antibiotic perturbations can lead to microbiome dysbiosis, characterized by acute or persistent imbalanced states of the commensal ecosystem. Dysbiosis has been associated with numerous human pathologies including inflammatory bowel disease, obesity, and gastrointestinal cancers.¹³ Post-antibiotic microbiome dysbiosis can also lead to the expansion of opportunistic pathogens in the gut, such as Clostridioides difficile.

Antibiotic use also enriches for antibiotic-resistant bacteria within the gut microbiome. In the context of war, killing any number of the enemy seems like a victory; however, like a hydra sprouting two heads after one is chopped off, repeated antibiotic exposures will make antibiotic-resistant bacteria stronger.¹⁴ Importantly, this is not limited to pathogens. The same evolutionary dynamics of selection and adaptation also drive increasing resistance in non-pathogenic species. Often, this resistance is encoded on mobile genetic elements, which can lead to more frequent and broader dissemination of resistance by horizontal gene transfer.

Diplomatic strategies

No matter how many bacteria-inhibiting drugs we develop, antibiotic resistance is never going away. The history of antibiotic use and resistance in pathogens has taught us that resistance is not a question of ‘if,’ but rather, only a matter of ‘when’.¹⁵ Instead, we must develop complementary strategies that enable us to better coexist with resistant bacteria while suppressing their virulence. New approaches draw on two key insights from microbial ecology: First, the real problem is not resistance alone, but resistance coupled with pathogenesis. Second, pathogenesis is not binary between “good” commensals and “bad” pathogens but a spectrum between them. For example, pathobionts like Escherichia coli can be harmless members of a healthy gut microbiome or a disease-causing gastrointestinal, urinary, or blood pathogen, depending on the host and environmental context, and the induced expression of specific repertoires of virulence factors. In contrast to the martial strategies of conventional antibiotic deployment for bacterial growth inhibition or killing, ecology-first strategies borrow from tenets of diplomacy and cooperation to attempt to mitigate antibiotic resistance by tilting bacteria away from pathogenesis towards avirulence and commensalism.

De-escalation (antibiotic stewardship): The back-and-forth between humans deploying new antibiotic drug classes, and bacteria evolving new resistance mechanisms, has been called an evolutionary arms race. That implies bacteria are a strategic enemy consciously responding to our moves with countermoves; however the expansion and spread of resistance is an automatic evolutionary response to the selective pressure imposed on bacteria by prolific antibiotic use. The development of more powerful antibiotics to eradicate resistant bacteria continues to escalate the antibiotic arms race. Instead, we should strive for de-escalation by controlling and reducing antibiotics use.

In clinical settings, stewardship programs encourage prudent use of antibiotics. They establish guidelines for “the optimal selection, dosage, and duration of antimicrobial treatment that results in the best clinical outcome for the treatment or prevention of infection, with minimal toxicity to the patient and minimal impact on subsequent resistance.”¹⁶ In conjunction, it’s critical to reduce antibiotic overuse and misuse. Overuse occurs when antibiotics are used unnecessarily, such as in patients with viral infections, non-infectious processes, bacterial infections that don’t require antibiotics, and bacterial colonization.¹⁷ It also occurs when medically important antibiotics (i.e. from classes important to human medicine) are used in food-producing animals to improve growth rates.¹⁸ Antibiotics are also frequently misused, such as when broad-spectrum antibiotics continue to be used even after culture data indicates the pathogen is not susceptible to that regimen or a narrower-spectrum compound would be just as effective. Phage therapy, which kills antibiotic-resistant pathogens using highly specific bacteriophages, is also a promising alternative to traditional antibiotics.

Disarmament (anti-virulence): At its root, the problem with antibiotic-resistant infections is not resistance per se but pathogenesis. An alternative to antibiotics are antivirulence therapeutics that disarm pathogens of the virulence factors pathogens produce to cause infection and evade the host immune response (e.g., toxins, adhesins, immune evasion and modulation factors, and siderophores).^19,20 Interestingly, anti-virulence strategies historically precede antibiotic use, with Emil von Behring developing an antiserum derived against diphtheria toxin in 1893. A related strategy, referred to as plasmid interference and plasmid curing, disarms pathogens at the genetic level by eliminating problematic plasmids that encode for virulence and antibiotic resistance genes.^21,22

No matter how many bacteria-inhibiting drugs we develop, antibiotic resistance is never going away. The history of antibiotic use and resistance in pathogens has taught us that resistance is not a question of ‘if,’ but rather, only a matter of ‘when’. Instead, we must develop complementary strategies that enable us to better coexist with resistant bacteria while suppressing their virulence.

These approaches have several distinct advantages compared to conventional antibiotics: First, because commensal bacteria generally don’t encode for virulence factors there’s less potential impact to the broader gut microbiome. Second, while antibiotics target central growth pathways, these strategies don’t destroy host bacterial populations outright. That may mean there may be less evolutionary pressure for the development of anti-virulence and plasmid-curing resistance. Though several anti-virulence agents have entered clinical trials, most are still in the preclinical stage.²⁰

Soft power (colonization resistance): Whether a pathobiont is a virulent pathogen or benign commensal can depend on its ecological context. Commensal microbiota can suppress the proliferation of incoming pathogens and the expansion of opportunistic pathobionts via several mechanisms of colonization resistance. These include nutrient competition, altering host environmental conditions, and enhancing the intestinal epithelial barrier.²³ By modulating the gut microbiome using probiotics and prebiotics, or replacing dysbiotic microbiota with those from healthy donors through fecal microbiota transplantation, we can exert a kind of soft power that influences pathobionts to adopt commensal lifestyles, rather than pathogenic ones.

For example, patients can be asymptomatically colonized for prolonged periods by toxigenic C. difficile. Our recent work has identified certain commensal gut species that protect against disease by suppressing C. difficile toxin production while allowing its stable growth and colonization in the gut.²⁴ By identifying such commensal-pathogen dynamics, we can design microbiome-targeting therapeutics that alter the gut microbiome in a way that steers pathogens toward avirulent states.

Conclusion

Like any good diplomatic strategy, the best approach to mitigate antibiotic resistance will be multi-pronged. When used in combination, many of the approaches above could reinforce each other: reducing antibiotic use increases the gut microbiome’s colonization resistance against C. difficile, and neutralizing the C. difficile toxins with antivirulence drugs bolsters the action of commensal species that suppress toxin production. Similar approaches may also be used beyond the gut microbiome, to address antibiotic-resistant infections from the oral, skin, and genital microbiomes. However, we stress that, although they are frequently based on well-established ecological principles and in vivo studies, the therapeutic potential of these approaches remains speculative. Few have been proven in the field and, if implemented, should be tailored to the specifics of each patient, pathogen, and disease.

We likely will always need targeted antibiotics to kill the deadliest human pathogens, especially in immunologically vulnerable patients. But, as in human diplomacy, we must strive to explore all other options to suppress pathogenesis and only resort to armed conflict as a last resort. Non-antibiotic strategies of de-escalation, disarmament, and soft power promise to be effective for patients in the short term, while conserving our antibiotic arsenal for those who need it most. By understanding and leveraging the ecological and evolutionary processes underlying antibiotic resistance, pathogenesis, and commensalism, we may be able to more sustainably and peacefully co-exist with the diversity of microbes that live in and on us.

References

1. Lettau L A (2000) The language of infectious disease: a light-hearted review. Clin Infect Dis 31, 734-738.
2. Larsson DGJ, Flach CF (2022) Antibiotic resistance in the environment. Nat Rev Microbiol 20, 257-269.
3. Knapp CW, Dolfing J, Ehlert PA, Graham DW (2010) Evidence of increasing antibiotic resistance gene abundances in archived soils since 1940. Environ Sci Technol 44, 580-587.
4. Crofts TS, Gasparrini AJ, Dantas G (2017) Next-generation approaches to understand and combat the antibiotic resistome. Nat Rev Microbiol 15, 422-434. 
5. Kwon JH,  Powderly WG (2021) The post-antibiotic era is here. Science 373, 471.
6. Benveniste R, Davies J (1973) Aminoglycoside antibiotic-inactivating enzymes in actinomycetes similar to those present in clinical isolates of antibiotic-resistant bacteria. Proc Natl Acad Sci U S A 70, 2276-2280.
7. Waglechner N, Culp EJ, Wright GD (2021) Ancient Antibiotics, Ancient Resistance. EcoSal Plus 9
8. D’Costa VM, McGrann KM, Hughes DW, Wright GD (2006) Sampling the antibiotic resistome. Science 311, 374-377.
9. Forsberg KJ, Reyes A, Wang B, Selleck EM, Sommer MOA et al. (2012) The shared antibiotic resistome of soil bacteria and human pathogens. Science 337, 1107-1111
10. Sender R, Fuchs S, Milo R (2016) Revised Estimates for the Number of Human and Bacteria Cells in the Body. PLoS Biol 14, e1002533.
11. Turnbaugh PJ,  Ley RE, Hamady M, Fraser-Liggett CM, Knight R et al. (2007) The human microbiome project. Nature 449, 804-810.
12. Gilbert JA, Blaser MJ, Caporaso JG, Jansson JK, Lynch SV et al. (2018) Current understanding of the human microbiome. Nat Med 24, 392-400.
13. Fishbein SRS, Mahmud B, Dantas G (2023) Antibiotic perturbations to the gut microbiome. Nat Rev Microbiol 21, 772-788.
14. Maccaro J (2021) Be Mindful of Your Metaphors about Microbes. mSphere 6, e0043121.
15. Boolchandani M, D’Souza AW, Dantas G (2019) Sequencing-based methods and resources to study antimicrobial resistance. Nat Rev Genet 20, 356-370, 
16. Gerding DN (2001) The search for good antimicrobial stewardship. Jt Comm J Qual Improv 27, 403-404.  
17. Doron S, Davidson LE (2011) Antimicrobial stewardship. Mayo Clin Proc 86, 1113-1123
18. U.S. Food & Drug Administration (2024) 2023 Summary Report On Antimicrobials Sold or Distributed for Use in Food-Producing Animals. [Accessed 17/10/2025]
19. Hotinger JA, Morris ST, May AE (2021) The Case against Antibiotics and for Anti-Virulence Therapeutics. Microorganisms 9.
20. Dickey SW, Cheung GYC, Otto M (2017) Different drugs for bad bugs: antivirulence strategies in the age of antibiotic resistance. Nat Rev Drug Discov 16, 457-471. 
21. Zhou Y, Yang Y, Li X, Tian D, Ai W, et al. (2023) Exploiting a conjugative endogenous CRISPR-Cas3 system to tackle multidrug-resistant Klebsiella pneumoniae. EBioMedicine 88, 104445.
22. Kamruzzaman M, Shoma S, Thomas CM, Partridge SR, Iredell JR, et al. (2017) Plasmid interference for curing antibiotic resistance plasmids in vivo. PLoS One 28, 12(2):e0172913.
23. Kamada N, Chen GY, Inohara N, Nunez G (2013) Control of pathogens and pathobionts by the gut microbiota. Nat Immunol 14, 685-690,  (2013).
24. Fishbein SRS, DeVeaux AL, Khanna S, Ferreiro AL, Liao J,  et al. (2025) Commensal-pathogen dynamics structure disease outcomes during Clostridioides difficile colonization. Cell Host Microbe 33, 30-41 e36.