Essential fatty acids disrupt the mycolic acid-rich cell envelope of clinical Nocardia isolates: A membrane-targeting approach to combat persistent infections

We evaluated five essential fatty acids (EFAs) against 82 clinical Nocardia isolates. α-Linolenic acid, γ-linolenic acid, eicosapentaenoic acid and docosahexaenoic acid (DHA) exhibited comparable activity (MIC50 / MIC90: 31.25/62.50 μM), corresponding to mass concentration ranges of 8.7 to 10.3 μg/mL for MIC50 and 17.4 to 20.6 μg/mL for MIC90.

However, arachidonic acid was markedly less active. Using DHA as a representative EFA, we showed that it rapidly disrupts the mycolic acid‑rich cell envelope, causing propidium iodide influx and ultrastructural damage, and achieves concentration‑dependent bactericidal killing within 1 h, a feat not observed with imipenem. Transcriptomic analysis revealed that surviving cells enter a state of metabolic sensitization, characterized by a maladaptive transcriptional response involving the downregulation of the proton-pumping Nuo complex, compensatory upregulation of the type II NADH dehydrogenase (Ndh), and a global induction of protein synthesis machinery.