Sulfonamide resistance as a global one health challenge

The Journal of Antibiotics https://doi.org/10.1038/s41429-026-00933-z PERSPECTIVE Sulfonamide resistance as a global one health challenge Sohail Ahmad1 1234567890();,: 1234567890();,: Received: 6 February 2026 / Revised: 1 May 2026 / Accepted: 14 May 2026 © The Author(s), under exclusive licence to the Japan Antibiotics Research Association 2026 Abstract Sulfonamide resistance is often viewed as a consequence of antibiotic misuse; however, growing evidence reveals its widespread distribution across humans, animals, and the environment. Escherichia coli exhibits sulfamethoxazole resistance of 44–57%, with 93% of isolates carrying sul1 or sul2, while sul4 has recently emerged in companion animals; many resistant strains harbor class 1 integrons linking sulfonamide resistance to other antibiotics. Although constructed wetlands remove 86–99% of sulfamethoxazole from wastewater, sul1 frequently persists ( ~ 10⁵ copies/mL), and in aquaculture, milkfish exposed to sulfamethoxazole (2 mg/L for 8 weeks) showed resistance increasing from 2.8% to 100% with survival reduced by up to 62%. These findings underscore sulfonamide resistance as an ecological challenge maintained across interconnected reservoirs, imposing a One Health approach to disrupt its transmission. Introduction Antimicrobial resistance (AMR) has been recognized as a major global One Health threat by the World Health Organization, arising largely from the widespread and often inappropriate use of antibiotics across human medicine, agriculture, and animal production systems [1, 2]. From a One Health perspective, the dissemination of antimicrobial resistance genes (ARGs) across interconnected human, animal, and environmental reservoirs highlights the need for coordinated intervention strategies [3]. In response, global policy frameworks including the WHO Global Action Plan on AMR and collaborative initiatives led by the Food and Agriculture Organization and the World Organization for Animal Health, under the broader Quadripartite alliance, have emphasized integrated monitoring of AMR and antimicrobial use across sectors [3]. These efforts are further strengthened by international recommendations such as the O’Neill Report, which advocate for improved stewardship, reduced environmental contamination, and the development of alternative strategies. Within these frameworks, coordinated surveillance systems increasingly utilize ARGs as molecular indicators of anthropogenic resistance * Sohail Ahmad 1 Department of Biochemistry, University of Malakand Chakdara, Dir Lower 18800, Pakistan dissemination, with sulfonamide resistance genes such as sul1 and sul2 widely recognized as robust environmental markers due to their association with class 1 integrons and human-driven pollution [4]. Although emerging variants such as sul4 are not yet formally incorporated into global monitoring schemes, their expanding detection across environmental and clinical settings highlights the evolving complexity of the sulfonamide resistome [4–6]. Sulfonamide resistance continues to pose a serious threat to global public health, extending beyond the realm of clinical medicine to veterinary and environmental domains [7–10]. Although traditionally viewed as a consequence of antibiotic misuse in human healthcare, emerging evidence suggests that the reality is much more multifaceted. Sulfonamide resistance genes, specifically the sul gene family, including sul1, sul2, sul3 and sul4, are now widely detected across a spectrum of reservoirs ranging from humans to livestock, companion animals, and down to environmental sinks [5, 11, 12]. The efficacy and low cost of these antibiotics have historically made them widely indispensable, while their long-term use cultivated a widespread resistome, particularly among Gram-negative bacteria [11, 13–15]. Here, we argue that sulfonamide resistance represents one of the clearest examples of a One Health failure, where environmental and veterinary reservoirs are not secondary, but central drivers of resistance persistence. As depicted in Fig. 1, under a One Health lens, it is evident that sulfonamide resistance is a shared risk where its use in one sector, such as a farm or a clinic, inevitably impacts all others [3, 11, 16]. S. Ahmad Mechanisms of Sulfonamide Resistance DHPS Enzyme MICROBIAL RESISTANCE Phe | Gly Phe-Gly insertion strictly hinders sulfonamide binding sul1 sul2 sul4 sul Genes on plasmid & integrons ANIMAL HEALTH pABA Sulfonamide Sulfonamide Resistance sul1 sul4 dfr folP folA HUMAN HEALTH sul3 ENVIRONMENTAL HEALTH mdtEF emrAB aadA Co-selection acrAB sul2 Antibiotic Pressure Heavy Metals Fig. 1 Sulfonamide resistance viewed through a One Health lens. This figure shows how sulfonamide resistance develops and spreads across interconnected human, animal, environmental, and microbial systems. The left panel highlights the One Health framework, where antibiotic use in humans and animals selects for resistant bacteria that move between hosts through direct contact, food production systems, and shared environments. Environmental compartments such as wastewater, soil, and aquatic ecosystems act as long-term reservoirs, allowing resistance genes to persist and re-enter human and animal populations. The microbial compartment emphasizes the role of diverse bacterial communities and horizontal gene transfer in maintaining and spreading resistance across sectors. The right panel illustrates the underlying mechanisms of sulfonamide resistance at the molecular and ecological levels. Resistance is primarily driven by sul genes (sul1–sul4), which encode altered dihydropteroate synthase (DHPS) enzymes that reduce sulfonamide binding while preserving folate synthesis. These genes frequently occur alongside other antimicrobial resistance determinants on mobile genetic elements, promoting multidrug resistance. Continuous antibiotic exposure and environmental stressors such as heavy metals further enhance the resistance through co-selection The distribution of these resistance factors globally illustrates an alarming level of interrelation between humans and animals (Table 1). For instance, livestock, particularly pigs, show a high frequency of sul1 and sul2 genes, which are often carried on mobile genetic elements like class 1 integrons and conjugative plasmids [11, 17]. Furthermore, poultry serves as a significant reservoir, with 58% of E. coli from broiler farms exhibiting sulfonamide resistance. Perhaps more concerning is the recent emergence of the sul4 gene variant in companion animals such as cats and dogs, which suggests a direct potential route for transmission to humans [11]. This resistance is not limited to industrial settings; even remote populations, such as Tibetan yak herders [13], show high rates of sulfamethoxazole resistance, supporting the idea that these genes can spread to the most isolated ecological niches. In this context, environmental reservoirs play a dual rol (...truncated)