Fatty Acid Biosynthesis in Bacterial Systems

Fatty acid biosynthesis in bacteria is a central metabolic pathway responsible for generating the lipid components of the cell membrane and for supplying acyl chains to diverse cellular processes. Bacteria employ a type II fatty acid synthase (FASII) system, in which discrete enzymes catalyse individual steps of chain initiation, elongation, dehydration and reduction. The initial condensation of acetyl‐coenzyme A (CoA) with malonyl‐ACP is performed by β-ketoacyl-ACP synthase III (FabH), followed by iterative cycles of β-ketoacyl reduction (FabG), dehydration (FabA or FabZ) and enoyl reduction (FabI or homologues) to produce saturated and unsaturated acyl-ACP species. Chain‐length and unsaturation are dictated by specific dehydratases and condensases, while acyl-ACP molecules also engage feedback regulators that fine-tune gene expression. Variation in FASII components among Gram-positive and Gram-negative bacteria underlies both pathogen-specific vulnerabilities and the capacity to scavenge exogenous fatty acids. The pathway is indispensable for bacterial viability, virulence and cell‐cell interactions, rendering it a prime target for novel antimicrobial agents and a template for biotechnological initiatives in biofuel and chemical production. Recent advances have illuminated mechanisms of antibiotic resistance, regulatory circuitry and enzyme structure–function relationships, reinforcing the global significance of understanding bacterial fatty acid synthesis.

Research from Nature Portfolio

Recent studies have demonstrated that Staphylococcus aureus can acquire high-frequency mutations in the fabD gene, encoding malonyl-CoA:ACP transacylase, which enable conditional bypass of de novo fatty acid synthesis when environmental lipids are available. These fabD variants maintain growth and virulence despite FASII inhibition, showing cross-resistance to multiple pathway inhibitors and retaining infectivity in murine infection models. This highlights how fatty acid-rich host niches can foster the emergence of multidrug-resistant staphylococcal strains and underscores the need for strategies that circumvent lipid salvage mechanisms in antimicrobial development.

Fatty Acid Biosynthesis in Bacterial Systems publication trend

The graph below shows the total number of articles in fatty acid biosynthesis in bacterial systems across all publications each year (not limited to Nature Index journals).

Technical terms

Type II fatty acid synthase (FASII): A dissociated enzyme system in bacteria, with each enzymatic activity encoded by a separate gene, responsible for stepwise fatty acid chain elongation.

Acyl carrier protein (ACP): A small, flexible cofactor that shuttles growing acyl chains between FASII enzymes via thioester linkage.

β-Ketoacyl-ACP synthase (FabH, FabF, FabB): Condensing enzymes that catalyse Claisen condensations between malonyl-ACP and acyl-CoA or acyl-ACP to initiate or elongate fatty acid chains.

Unsaturated fatty acids (UFAs): Fatty acids containing one or more double bonds introduced by dehydratase/isomerase enzymes (e.g. FabA) during elongation.

Exogenous fatty acids: Fatty acids sourced from the environment or host, which some bacteria can incorporate directly into membrane lipids to bypass FASII.

References

1. Antagonist Targeting the Species‐Specific Fatty Acid Dehydrogenase/Isomerase FabX for Anti‐H. pylori Infection. Advanced Science (2025).
2. Environmental fatty acids enable emergence of infectious Staphylococcus aureus resistant to FASII-targeted antimicrobials. Nature Communications (2016).
3. Roles of the FabA and FabZ β-Hydroxyacyl-Acyl Carrier Protein Dehydratases in Escherichia coli Fatty Acid Biosynthesis*. Journal of Biological Chemistry (1996).
4. Enoyl-Acyl Carrier Protein Reductase (fabI) Plays a Determinant Role in Completing Cycles of Fatty Acid Elongation in Escherichia coli (∗). Journal of Biological Chemistry (1995).
5. How Bacterial Pathogens Eat Host Lipids: Implications for the Development of Fatty Acid Synthesis Therapeutics*. Journal of Biological Chemistry (2015).
6. β-Ketoacyl-Acyl Carrier Protein Synthase III (FabH) Is Essential for Bacterial Fatty Acid Synthesis*. Journal of Biological Chemistry (2003).
7. Regulation of Fatty Acid Elongation and Initiation by Acyl-Acyl Carrier Protein in Escherichia coli (∗). Journal of Biological Chemistry (1996).