Hansen's Disease Antimicrobial Resistance Profiles
For three leprosy drug targets, HARP models every possible amino acid substitution and predicts how each one changes protein stability, interactions and dynamics. The flowchart below shows how the resource was built and how you can use it.
Building the database · three drug targets · nine protein chains · 80,902 mutations
MODELLER · Vivace pipeline
Published resistance mutations
Every residue changed to all 19 other amino acids
ConSurf · SDM2 · Arpeggio
From each mutated residue
Consensus scoring · one overall impact for every mutation
Qualitative outcomes from every tool and residue property
Each destabilising or stabilising term scores one
Destabilising terms minus stabilising terms
High, moderate or low impact · 30% / 63% / 6%
Using HARP · four ways in · 61 features for every mutation
Multidrug therapy for leprosy combines three drugs, each with bacteriostatic, bactericidal or anti-inflammatory activity. The bacteriostatic drug dapsone acts on dihydropteroate synthase (DHPS), an enzyme that Mycobacterium leprae needs to make folic acid. Missense mutations in the dapsone-binding region of DHPS cause dapsone resistance in leprosy.
The bactericidal drug rifampicin acts on RNA polymerase (RNAP), the enzyme that carries out transcription in Mycobacterium leprae. Mutations in the rifampicin-binding site, in the active-centre cleft of the RNAP complex, cause rifampicin resistance.
The bactericidal and anti-inflammatory drug clofazimine has no known target in Mycobacterium leprae, and clofazimine resistance is rare, so it is not included in HARP. The second-line bactericidal drug ofloxacin acts on DNA gyrase (GYR), and mutations in its binding site cause ofloxacin resistance.
There are no rapid experimental methods to link mutations with drug resistance in leprosy. Choosing another treatment for a drug-resistant case depends on finding mutations that have already been validated in the mouse footpad model, and there was no structural information on newly emerging mutations.
Over three decades, Professor Sir Tom Blundell's laboratory in the Department of Biochemistry, University of Cambridge, has developed software that predicts the impacts of mutations from protein sequence and structure. HARP applies these tools to every possible substitution in DHPS, RNAP and GYR.
HARP is intended for research use. Its name honours Professor Sir Tom Blundell's early career and interest in music, and follows other tools and databases from the group that are named after composers (Chopin, Mabellini) or musical terms (Tible, Arpeggio).
We thank the Structural Biology and Biocomputing Group for their contributions, and Hope Rises International (formerly American Leprosy Missions) for funding this work.
