Targeting bacterial phospholipids and their synthesis pathways for antibiotic discovery

Bacterial infections in humans and animals caused by multidrug-resistant (MDR) pathogens pose a serious threat to public health. New antibacterial targets are extremely urgent to solve the dilemma of cross-resistance. Phospholipids are critical components in bacterial envelopes and involve diverse crucial processes to maintain homeostasis and modulate metabolism. Targeting phospholipids and their synthesis pathways has been largely overlooked because conventional membrane-targeted substances are non-specific with cytotoxicity. In this review, we first introduce the structure and physiological function of phospholipids in bacteria. Subsequently, we describe the chemical diversity of novel ligands targeting phospholipids, structure-activity relationships (SAR), modes of action (MOA), and pharmacological effects. Finally, we prospect the advantage of bacterial phospholipids as promising antibacterial targets. In conclusion, these findings will shed light on discovering and developing new antibacterial drugs to combat MDR bacteria-associated infections. •Phospholipids and their metabolism pathways are essential for bacterial membrane homeostasis, serving as promising antibacterial targets.•The versatile scaffolds of phospholipids ligands offers potential antibacterial agents to combat emerging multidrug-resistant bacteria.•The thermodynamic profile is beneficial for design and optimization of membrane-targeting compounds.