Novel antibacterials

• What is the average cost of drug development?


  £1 Billion - £3 Billion
• What is the main global threat mentioned in the study material?

  Antimicrobial Resistance
• Why is there less investment in antimicrobial research compared to oncology research?

  There is 34x more venture investment in oncology than in antimicrobials
• How many clinical-stage breast cancer projects are there compared to antibacterial projects?

  160 vs. 64
• Who drives antimicrobial research in the current commercial landscape?

  Academia and small biotechs
• What is the major hurdle for developing new antimicrobials?

  Efflux-mediated resistance
• Why have no efflux pump inhibitors (EPIs) made it to clinical development?

  Due to toxicity and lack of structural insights
• What is the new paradigm for developing antimicrobials that overcome efflux resistance?

  Designing antimicrobials that block their own efflux while maintaining activity
• What is the key difference in efflux pump binding sites between E. coli and P. aeruginosa?

  AcrB in E. coli, MexB in P. aeruginosa
• What is the strategy for overcoming efflux resistance?

  Incorporating EPI characteristics directly into antibiotics
• What are the key benefits of the ERB technology platform?

  Compatible with all antibiotic classes, new chemical entities with strong IP protection, meets FDA priority requirements
• What is the current market share of fluoroquinolones in the global antibiotics market?

  17%
• Why has the use of fluoroquinolones declined?

  Resistance due to efflux
• What is the goal of applying ERB technology to fluoroquinolones?

  To restore their efficacy
• What are the ESKAPEE pathogens that the ERB-fluoroquinolones target?

  Enterococcus faecalis (VRE), Staphylococcus aureus (MRSA), Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp., E. coli
• What was the initial hit compound for the ERB-fluoroquinolone program?

  ML-77-005
• How did the activity of ML-77-005 compare to ciprofloxacin?

  It showed equivalent activity in sensitive S. aureus strains but superior activity in resistant strains
• What was the key insight from the structure-activity relationship (SAR) studies?

  Hydrophobicity is crucial for substrate-inhibitor character in the NorA efflux pump
• What was the name of the optimized lead compound?

  ML-83-009
• What was the key limitation of ML-83-009?

  It lacked NorA inhibition despite improved Gram-negative activity
• What was the name of the advanced lead compound?

  KSN-82-L22
• What was the key characteristic of KSN-82-L22?

  It exhibited EPI character but required further optimization for P. aeruginosa activity
• What were the two lead candidate series identified for further development?

  KSN-BL-7 series for MDR Gram-positive infections, KSN-L22 series for broad-spectrum Gram-positive and Gram-negative infections
• What were the key preclinical findings for the ERB-fluoroquinolone candidates?

  Potent inhibition of both wild-type and mutant bacterial gyrases, broad-spectrum efficacy against Gram-positive and Gram-negative pathogens, low potential for resistance development
• What was the maximum dose of the ERB-fluoroquinolone candidates that showed no observed toxicity in preclinical studies?

  400 mg/kg
• What was the oral bioavailability of the ERB-fluoroquinolone candidates in mice?

  83%
• What is the key focus for the next steps in the development of the ERB-fluoroquinolone candidates?

  Further optimizing compounds for P. aeruginosa and clinical advancement
• What are the key challenges and opportunities in antimicrobial drug development?

  Challenges:

  • High cost of development (£1-3 billion)
  • Antimicrobial resistance, especially efflux-mediated resistance
  • Less investment in antimicrobial research compared to oncology
  • Fewer clinical-stage antimicrobial projects compared to oncology

  
  

  Opportunities:

  • Innovative approaches like the ERB technology platform
  • Potential to restore efficacy of existing antibiotic classes
  • Meeting FDA priority requirements (e.g., GAIN Act)
  • Strong IP protection for new chemical entities
• What are the key features and benefits of the ERB technology platform?

  Key Features:

  • Acts as substrate inhibitors
  • Resistant to efflux
  • Maintains high intracellular concentrations

  
  

  Key Benefits:

  • Compatible with all antibiotic classes
  • Provides new chemical entities with strong IP protection
  • Meets FDA priority requirements (e.g., GAIN Act)
  • Applied to fluoroquinolones and antifungals to overcome efflux resistance
• What are the key steps in the development of the ERB-fluoroquinolone candidates?

  • Initial hit compound: ML-77-005
  • Structure-activity relationship (SAR) studies to enhance activity
  • Optimized lead: ML-83-009
  • Advanced lead: KSN-82-L22
  • Lead candidate series identified: KSN-BL-7 and KSN-L22
  • Preclinical findings: Potent inhibition of wild-type and mutant bacterial gyrases, broad-spectrum efficacy, low resistance potential
  • Favorable preclinical pharmacokinetics and safety profile
• What are the next steps for the development of the ERB-fluoroquinolone candidates?

  • Further optimize compounds for improved activity against Pseudomonas aeruginosa
  • Advance lead candidates to clinical development