Table 1 Comparison of Traditional vs Alternate pathways
From: Antibiotics re-booted—time to kick back against drug resistance
Traditional pathway | Alternate pathway | |
|---|---|---|
1. Compounds | • Commercial ‘optimised diversity’ of ‘soft focus’ (polar) libraries • Pharma and biotech proprietary libraries • Screening of natural product extracts leading to isolated natural products • Existing antibiotic scaffolds & chemotypes amenable to chemical modification • Scaffold from metagenomic analysis from ‘non-culturable’ micro-organisms • Micro-environment tailored culture and screening methods • Chemical diversity from global academic collections • miRNA • Innate immune modulators | • Microbial metabolites • Phage enzymes and delivery systems • Antibodies against virulence factors • Innate immune modulators |
2. Compound progression | a. In vitro i. Screening in culture broth for growth inhibition ii. Determination of MICs and MBCs in broth iii. Effect of serum and/or lung surfactant on activity iv. ADME/T b. In vivo i. Rodent & non-rodent PK ii. Immunosuppressed (cyclophosphamide) murine thigh infection model iii. Additional immunosuppressed murine infection models iv. Toxicology | a. In vitro i. MICs in whole blood or emulsified tissue treated to prevent opsonisation of bacteria or isolated from knockout mice deficient for select pathways that drive rapid bacterial clearance ii. Combination therapy with existing antibiotics iii. ADME/T b. In vivo i. Rodent & non-rodent PK ii. Immunocompetent infection models of drug alone vs. drug with adjuvant combinations iii. Toxicology |
3. Clinical Safety | SAD/MAD (Phase I) | SAD/MAD (Phase 1a) |
4. Clinical PK/PD | a. Phase 1b Human challenge trials using a non-virulent, antibiotic-susceptible, low grade pathogen | |
5. Clinical PoC | Phase II | Phase II |
