Design and synthesis of modified peptide antibiotics of the vancomycin family

The ability of bacteria to constantly evolve new methods of resistance to antibacterial therapies represents a constant challenge in medicine. Emergence of strains of enterococci and S. Aureus that show resistance to vancomycin is an alarming phenomenon, as vancomycin represents the last line of defence against pathogens with a significant level of resistance to all other available therapies, methicillin resistant S. Aureius (MRSA) being a prime example of such a pathogen. Vancomycin has a number of significant advantages as a drug therapy. It exploits a target that is not found in the host cells, the cell wall. It does this by inhibiting transpeptidation, which blocks murein biosynthesis, destabilising the cell wall and allowing the internal osmotic pressure of the cell to cause the cell membrane to rupture, killing the cell. The target of vancomycin is on the outside of the cell, so it is not affected by the membrane bound efflux pumps that induce multi-drug resistance. Therefore the only mechanism of resistance available is alteration of the target. Two such resistance mechanisms exist and if these can be overcome, the analogues of vancomycin that achieve this should be less prone to drug resistance than any other existing therapy. This work represents the first step towards such a goal, and is the first example of the application of rational drug design to complex natural product drugs, like vancomycin. This project used an X-ray crystal structure of vancomycin complexed to a mimic of the cell wall peptide. This structure was used in conjunction with the de notvo design program SPROUT as the basis for molecular design, in order to create analogues of vancomycin that were predicted to offer increased affinity for the tripeptide cell wall mimic. Five such designed molecular templates were created and assessed for synthetic feasibility. One of these templates was selected and synthesised. This analogue prompted a second design phase which produced a further three molecular templates, two of which were also synthesised. The efficiency of these modified vancomycins to bind the target tripeptide was assessed using nanoelectrospray ionisation - mass spectrometry. It was found that all the analogues produced offered increased binding efficiency as compared to vancomycin tested under the same conditions. This work paves the way to exploring the use semi-synthetic derivatives of vancomycin as novel therapeutic agents.

Name dc:type.qualificationname

Ph.D

Level dc:type.qualificationlevel

doctoral

Grantor dc:publisher.institution

University of Leeds

Year dc:date.issued

2008

Author dc:creator

• Bone, Philip Andrew

Advisors dc:contributor.advisor

• Johnson, A. Peter
• Fishwick, Colin W. G.

Identifier

uk.bl.ethos.514008

OAI identifier oai:identifier

oai:etheses.whiterose.ac.uk:614