Glycopeptide and Lipopeptide Antibiotics With Potent Activity Against Multi-Drug Resistant Pathogenic Bacteria Responsible for UTI, cSSSI and CAP/NP Infections. — ASN Events
  1. Schedule
  2. Division 4 – Microbial Genetics, Physiology and Pathogenesis
  3. Mini Symposium - Antimicrobials
  4. Glycopeptide and Lipopeptide Antibiotics With Potent Activity Against Multi-Drug Resistant Pathogenic Bacteria Responsible for UTI, cSSSI and CAP/NP Infections.

Glycopeptide and Lipopeptide Antibiotics With Potent Activity Against Multi-Drug Resistant Pathogenic Bacteria Responsible for UTI, cSSSI and CAP/NP Infections. (#77)

Matthew A Cooper 1 , Mark A Blaskovich 1 , Tanya Bradford 1 , Mark S Butler 1 , Bernd Becker 1 , Mu Cheng 1 , Alberto B Silva 1 , David Edwards 1 , Karl Hansford 1 , Johnny Xiao Huang 1 , Tomislav Karoli 1 , Angela Kavanagh 1 , June C Lee 1 , Fredrik Lindahl 1 , Craig A Muldoon 1 , David L Paterson 1 , Ruby Pelingon 1 , Rajaratnam Premraj 1 , Soumya Ramu 1 , Jason Roberts 1 , Hanna Sidjabat 1 , Azzah Suboh 1 , Karen Wong 1 , Benjamin Yakimoff 1 , Zyta Ziora 1 , Johannes Zuegg 1
  1. University of Queensland, St Lucia, QLD, Australia

Background:

The paucity of drugs for systemic treatment of multi-drug resistant bacterial infections is one of the most pressing health issues currently facing humankind. New approaches to antibiotic discovery are needed.

Methods:

We have designed lipopeptide and glycopeptide derivatives selective for bacterial membranes over mammalian membranes. We are developing these for the treatment of community-acquired and nosocomial infections; complicated skin and skin structure (cSSSI), urinary tract, and pneumonia (CAP/NP).

Results:

In the Gram–ve active lipopeptide series, we have identified compounds active against multi-drug resistant E. coli, P. aeruginosa, K. pneumonia, and A. baumannii,including colistin-resistant and NDM-1 strains.

In the Gram+ve active glycopeptide series, compounds are 20 to 100-fold more active (MIC <3 ng/mL) than vancomycin (MIC ~ 1 ug/mL), and are bactericidal. They have excellent plasma and microsomal stability, show minimal inhibition of CYP450 enzymes, are clear in Ames mutagenicity testing, and show no cytotoxicity in mammalian cell MTT assays at concentrations exceeding 1000 times the MIC.   Mouse pharmacokinetic profiles are consistent with once daily dosing in man and the compounds show equivalent or superior efficacy to the reference antibiotics vancomycin and daptomycin in multiple infection models, including MRSA and S. pneumoniae thigh infection, blood bacteremia, sepsis, and lung infection.  For example, potent activity is observed with a single sub-cutaneous 10 mg/kg dose in the MRSA thigh infection model, showing equivalent efficacy to 200 mg/kg vancomycin, with greater than 100,000-fold reduction in bacterial load (cfu/thigh) at 24h.  The compounds are also active in lung infection models (where daptomycin fails), with 100% survival in a lethal dose study with a MDR S. pneumonia strain.

Conclusion

Membrane targeting is a novel approach showing early promise that could lead to new candidate antibiotics or to ‘revitalise’ old drugs with resistance and/or toxicity profile liabilities.

Contact details:  Professor Matthew A. Cooper, m.cooper@uq.edu.au +61 7 334 62045