Exogenous fatty acid metabolism in bacteria

Area of Science:

• Microbiology
• Biochemistry
• Drug Discovery

Background:

• Bacterial type II fatty acid synthesis (FASII) is a validated target for novel antibiotic development.
• Bacteria possess diverse mechanisms to incorporate exogenous fatty acids, impacting their survival and potential for antibiotic resistance.
• Some bacteria can bypass FASII inhibition by utilizing exogenous fatty acids, posing a challenge for antibiotic strategies.

Purpose of the Study:

• To elucidate the distinct mechanisms bacteria employ to activate and incorporate exogenous fatty acids.
• To investigate why only certain bacteria, like Lactobacillales, can fully bypass FASII inhibition using exogenous fatty acids.
• To explore the implications of these mechanisms for antibiotic development and bacterial adaptation.

Main Methods:

• Comparative analysis of exogenous fatty acid activation pathways across different bacterial groups (Gammaproteobacteria, Gram-negative, Gram-positive bacteria).
• Examination of the metabolic fates of activated exogenous fatty acids (acyl-CoA, acyl-ACP, acyl-phosphate).
• Review of conditions leading to FASII downregulation or bypass, including FASII inhibition and biofilm growth.

Main Results:

• Gammaproteobacteria (e.g., E. coli) convert exogenous fatty acids to acyl-CoA, maintaining a separate pool from acyl-ACP.
• Some Gram-negative bacteria convert exogenous fatty acids to acyl-ACP, integrating them into the endogenous pathway.
• Gram-positive bacteria convert exogenous fatty acids to acyl-phosphates, with subsequent conversion to acyl-ACP possible.
• Only Lactobacillales can completely bypass FASII inhibition by utilizing exogenous fatty acids for phospholipid synthesis.
• Other bacteria exhibit partial FASII downregulation or require FASII for essential metabolite synthesis, preventing complete bypass.

Conclusions:

• Bacterial strategies for incorporating exogenous fatty acids vary significantly, influencing their ability to circumvent FASII inhibition.
• The unique ability of Lactobacillales to fully bypass FASII highlights a specific metabolic adaptation with implications for antibiotic resistance.
• Understanding these diverse pathways is critical for designing effective antibiotics targeting FASII and for predicting bacterial adaptive responses.