New polymyxin antibiotics for old problems: addressing nephrotoxicity and resistance

Slingerland, C.J. (2024)

Doctoral Thesis

Polymyxins are clinically used antibiotics, discovered in mid-20th century. Once abandoned due to excessive nephrotoxicity, they are now used increasingly to address infections caused by multi-drug resistant Gram-negative bacteria.

In this thesis, we describe the development and synthesis of analogues of polymyxin, aimed at reducing its associated nephrotoxicity. Analogues were made by semisynthesis, with modifications introduced mostly in the exocyclic portion of the molecule. Especially the introduction of a disulfide bond within the linked lipid helped in reducing the toxicity of the molecules, as evidenced by testing on proximal tubule epithelial cells. For most potent analogues, the antimicrobial activity was completely retained.

In addition, this thesis describes studies on the mechanism of action of polymyxin, mostly based on the full stereoisomer of polymyxin B4. This analogue lacks antimicrobial activity, indicating its original stereochemistry to be of utmost importance for its use as an antibiotic.

Hybrids based on polymyxin B derivatives are described, addressing non-conventional targets. A hybrid with vancomycin (typically active on Gram-positive bacteria only) shows activity on Gram-negative bacteria. A polymyxin-based hybrid coupled to a peptide with a beta-hairpin motif addresses Gram-negative bacteria, presumably by binding to outer membrane protein BamA.

• Polymyxins
• Nephrotoxicity
• Antibiotics
• Gram-negative bacteria
• Semisynthesis
• Mechanism of action
• Lipopolysaccharide
• Polymyxin-based hybrids

• All authors: Slingerland, C.J.
• Supervisor: Martin, N.I.
• Co-supervisor: Innocenti, P.
• Committee: Meijer, A.H.; Briegel, A.; Overkleeft, H.S.; Albada, H.B.; Veldhuizen, E.J.A.
• Qualification: Doctor (dr.)
• Awarding Institution: Institute of Biology Leiden (IBL), Faculty of Science, Leiden University
• Date: 2024-02-28