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The primary concern is the indiscriminate biodistribution of traditional antimicrobials, which may result in dose-limiting off-target toxicity, thereby impacting beneficial commensal microbiomes and causing detrimental effects including dysbiosis ( In addition to their cytotoxic effects, many small-molecule agents exhibit insufficient penetration into critical sanctuary sites, including granulomas, the blood-brain barrier (BBB), and various intracellular compartments, where pathogens can persist and facilitate relapse (Pardridge, 2020

Additionally, the upregulation of ribosomal proteins enhances protein synthesis, and glycolytic enzyme overexpression boosts energy production, collectively contributing to the parasites survival and resistance ( A comparative overview of resistance mechanisms across major antileishmanial drugs is provided in Table 3, highlighting recurrent themes such as transporter upregulation, metabolic adaptations, and genetic mutations

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