In vitro Insights of Exogenous Fatty acids and FASII Inhibitors on Lipid Profiles and Antibiotic Susceptibilities in Staphylococcus aureus

The prevalence of hospital-acquired methicillin-resistant Staphylococcus aureus (MRSA) infections is on the rise, primarily due to the rapid development of resistance mechanisms by S. aureus against commonly used antibiotics.¹ Daptomycin, the last-resort antibiotic for MRSA, has encountered challenges as studies reveal acquired resistance by S. aureus.² FASII is a distinct metabolic pathway associated in synthesis of fatty acids through a series of specific enzymes in S. aureus, serving as precursors for phospholipid (PL) synthesis. Recently, FASII has become a target for antimicrobial drug development.³ While FASII inhibitors have gained popularity for inhibiting endogenous PL synthesis in S. aureus, the organism's ability to assimilate exogenous fatty acids (exo-FAs) at infection sites however has enabled it to evade the impact of FASII inhibitors.⁴ In this study we employed microbiological techniques and liquid chromatography-mass spectrometry (LCMS) methods as complementary approaches to correlate changes in daptomycin susceptibilities and phospholipid profiles of S. aureus strains in the presence of exo-FAs and FASII inhibitors in vitro. The combined impact of exo-FAs and FASII inhibitors was investigated to understand bacterial resistance dynamics. The insights gained from this research will be valuable in enhancing the development of more effective antibacterial strategies and mechanisms of resistance pathways in S. aureus.

References

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3. Hafkin, B.; Kaplan, N.; Murphy, B., Efficacy and Safety of AFN-1252, the First Staphylococcus-Specific Antibacterial Agent, in the Treatment of Acute Bacterial Skin and Skin Structure Infections, Including Those in Patients with Significant Comorbidities. Antimicrobial Agents and Chemotherapy 2016, 60 (3), 1695-1701.

4. Hines, K. M.;  Alvarado, G.;  Chen, X.; Gatto, C.;  Pokorny, A.;  Alonzo, F.; Wilkinson, B. J.; Xu, L., Lipidomic and Ultrastructural Characterization of the Cell Envelope of Staphylococcus aureus Grown in the Presence of Human Serum. mSphere 2020, 5 (3), e00339-20.