Université Paris Cité, Institut Cochin, INSERM, U1016, CNRS, UMR8104, Paris, France.
Molecular Microbiology and Structural Biochemistry, CNRS, UMR5086, Université de Lyon, Lyon, France.
Nat Commun. 2024 Oct 4;15(1):8593. doi: 10.1038/s41467-024-52637-3.
In Streptococcus pyogenes, the type II fatty acid (FA) synthesis pathway FASII is feedback-controlled by the FabT repressor bound to an acyl-Acyl carrier protein. Although FabT defects confer reduced virulence in animal models, spontaneous fabT mutants arise in vivo. We resolved this paradox by characterizing the conditions and mechanisms requiring FabT activity, and those promoting fabT mutant emergence. The fabT defect leads to energy dissipation, limiting mutant growth on human tissue products, which explains the FabT requirement during infection. Conversely, emerging fabT mutants show superior growth in biotopes rich in saturated FAs, where continued FASII activity limits their incorporation. We propose that membrane alterations and continued FASII synthesis are the primary causes for increased fabT mutant mortality in nutrient-limited biotopes, by failing to stop metabolic consumption. Our findings elucidate the rationale for emerging fabT mutants that improve bacterial survival in lipid-rich biotopes, but lead to a genetic impasse for infection.
在酿脓链球菌中，II 型脂肪酸（FA）合成途径 FASII 受到 FabT 抑制剂与酰基-酰基载体蛋白结合的反馈控制。尽管 FabT 缺陷赋予了动物模型中的毒力降低，但 fabT 自发突变体在体内出现。我们通过描述需要 FabT 活性的条件和机制以及促进 fabT 突变体出现的条件和机制来解决这一矛盾。fabT 缺陷导致能量耗散，限制了突变体在人组织产物上的生长，这解释了感染过程中 FabT 的需求。相反，出现的 fabT 突变体在富含饱和 FA 的生境中表现出更好的生长，在这些生境中，持续的 FASII 活性限制了它们的掺入。我们提出，在营养有限的生境中，膜的改变和持续的 FASII 合成是导致 fabT 突变体死亡率增加的主要原因，因为它们无法停止代谢消耗。我们的发现阐明了在富含脂质的生境中提高细菌存活率但导致感染遗传僵局的出现 fabT 突变体的基本原理。
