Natural Products Against Mycoplasma gallisepticum: Emerging Alternatives to Combat Antimicrobial Resistance

Antimicrobial resistance in Mycoplasma gallisepticum (MG), a primary causative agent of chronic respiratory disease in poultry, has reached alarming levels, underscoring the urgent need for alternative strategies. Natural products have emerged as promising candidates owing to their multi-target mechanisms of action. This review synthesizes current evidence on natural anti-MG agents, critically appraising their in vitro and in vivo efficacy, molecular mechanisms, and translational potential. A mechanistic taxonomy is proposed for distinguishing direct pathogen-directed mechanisms (membrane disruption, adhesion inhibition, virulence factor neutralization) from indirect host-directed mechanisms, notably NF-κB/MAPK pathway modulation and gut–lung axis immunoregulation. Emphasis is placed on anti-infective polypharmacology, exemplified by luteolin’s dual inhibition of the TatD virulence factor and host inflammatory cascades. The gut–lung axis represents a novel therapeutic frontier, with Bacillus subtilis KC1 controlling respiratory mycoplasmosis through intestinal microbiome remodeling and systemic AhR activation. Despite encouraging efficacy data, critical knowledge gaps persist, including a scarcity of rigorous in vivo trials under commercial conditions, incomplete mechanistic characterization, and challenges in standardizing complex natural product formulations. Natural products are best positioned not as wholesale antibiotic replacements but as integral components of integrated, antibiotic-sparing strategies aligned with antimicrobial stewardship and One Health principles.