Structure and Function of the Two-Component Cytotoxins of Staphylococcus aureus - Learnings for Designing Novel Therapeutics

• Published in: Advances in experimental medicine and biology Vol. 966; p. 15
• Main Authors: Badarau, Adriana, Trstenjak, Nikolina, Nagy, Eszter
• Format: Journal Article
• Language: English
• Published: United States 2017
• Subjects: Animals; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - therapeutic use; Bacterial Proteins - antagonists & inhibitors; Bacterial Proteins - chemistry; Bacterial Proteins - metabolism; Drug Design; Hemolysin Proteins - antagonists & inhibitors; Hemolysin Proteins - chemistry; Hemolysin Proteins - metabolism; Humans; Leukocidins - antagonists & inhibitors; Leukocidins - chemistry; Leukocidins - metabolism; Models, Molecular; Molecular Targeted Therapy; Protein Conformation; Staphylococcal Infections - drug therapy; Staphylococcal Infections - microbiology; Staphylococcus aureus - drug effects; Staphylococcus aureus - metabolism; Staphylococcus aureus - pathogenicity; Structure-Activity Relationship; Virulence; Oligomerization; Beta-barrel pore; Bi-component toxins; Leukocidins; Staphylococcus aureus
• ISSN: 0065-2598
• DOI: 10.1007/5584_2016_200

Staphylococcus aureus can produce up to five different bi-component cytotoxins: two gamma-hemolysins HlgAB and HlgCB, and leukocidins SF-PV (Panton Valentine leukocidin), ED (LukED) and GH (LukGH, also called LukAB). Their major function in S. aureus pathogenesis is to evade innate immunity by attacking phagocytic cells and to support bacterial growth by lysing red blood cells. The five cytotoxins display different levels of amino acid sequence conservation (30-82%), but all form a remarkably similar beta-barrel type pore structure (greatly resembling the mono-component toxin alpha-hemolysin) that inserts into the target cell membrane leading to necrotic cell death. This review provides an overview of the culmination of decades of research on the structure of these toxins, their unique sequence and structural features that helps to explain the observed functional differences, such as toxin potency towards different cell types and species, receptor specificity and formation of functional non-cognate toxin pairs. The vast knowledge accumulated in this field supports novel approaches and the design of therapeutics targeting these cytotoxins to tame virulence and fight S. aureus infections.