Novel antimicrobial strategies to treat multi-drug resistant Staphylococcus aureus infections

Abstract

Antimicrobial resistance is a major obstacle for the treatment of infectious diseases and currently represents one of the most significant threats to global health. Staphylococcus aureus remains a formidable human pathogen with high mortality rates associated with severe systemic infections. S. aureus has become notorious as a multidrug resistant bacterium, which when combined with its extensive arsenal of virulence factors that exacerbate disease, culminates in an incredibly challenging pathogen to treat clinically. Compounding this major health issue is the lack of antibiotic discovery and development, with only two new classes of antibiotics approved for clinical use in the last 20 years. Combined efforts from the scientific community have reacted to the threat of dwindling treatment options to combat S. aureus disease in several innovative and exciting developments. This review describes current and future antimicrobial strategies aimed at treating staphylococcal colonization and/or disease, examining therapies that show significant promise at the preclinical development stage to approaches that are currently being investigated in clinical trials.

FIGURE 1

Structures of recently developed lipoteichoic acid (LTA), FtsZ and FabI inhibitors.

FIGURE 2

Structure and mechanism of action of new naturally occurring antibiotics. Cell wall synthesis begins with the formation of UDP‐MurNAc action through the action of MurA and MurB. The pentapeptide is subsequently added to UDP‐MurNAc acid by the enzymes MurC‐F to form the phosphor‐MurNAc‐pentapeptide. This is ligated to the lipid carrier undecaprenyl‐diphosphate by MraY to form the lipid I precursor. The addition of UDP‐GlcNAc by MurG finally results in the formation of lipid II. FemX then adds the first glycyl unit, FemA the second and third, and FemB the fourth and fifth to complete the addition of the pentaglycine cross bridge. Final structural modification of lipid II, such as deamination of D‐Glu on the stem peptide, is performed by MurT and GatD. The completed lipid II molecule is subsequently flipped to the outer membrane through the action of MurJ/SAV1754 which is blocked by the action of humimycin A and humimycin B. The final stage of cell wall synthesis is carried out by penicillin‐binding proteins (PBPs), which incorporate lipid II into the growing peptidoglycan sacculus through transglycosylation and transpeptidation reactions. This is prevented through the action of malacidin A and teixobactin which bind to extracellular lipid II and prevent PBP binding. As peptidoglycan matures it undergoes structural reconfiguration through the action of autolysins. The binding of complestatin and corbomycin to conserved peptidoglycan residues prevents the binding of autolysins thus inhibiting cell wall turnover. After the addition of lipid II into the cell wall, undecaprenyl diphosphate is recycled to undecaprenyl phosphate by UppP and used as a precursor for wall teichoic synthesis. TarO and TarA catalyse the formation of the disaccharide linker which is conjugated to undecaprenyl diphosphate. Next two glycerol phosphate residues are added by TarB which sets the stage for teichoic acid polymerization. Repeating subunits of ribitol phosphate are added by TarF and TarL. The completed teichoic acid is flipped to the outer membrane by TarGH and incorporated in the cell wall by the teichoic ligase LcpA. Importantly, teixobactin has been shown to bind to multiple cell wall and teichoic acid precursors including lipid III and undecaprenyl diphosphate and lipid I. WAP‐8294A2 is thought to cause menaquinone‐dependant membrane lysis. Lugdunin is thought to cause membrane disruption through an unknown mechanism of action.

FIGURE 3

Summary of novel strategies currently being developed to treat multidrug resistant Staphylococcus aureus infections.