A new antivirulence approach against pathogenic bacteria dr shabeel pn

Corporate overview Biopharmaceutical company specialized in antibacterial drug discovery for prevention of severe infections especially nosocomial Portfolio of intellectual property Virulence validated targets – Preclinical development of inhibitors small molecules Experienced management and R&D team - Prestigious academic partnerships - 3 R&D grants (ANVAR, Genhomme, BioSecurity) 20 Employees: 1 CEO/CSO, 1 director MedChem, 9 biologists/biochemists, 7 medicinal chemists (8 Ph.D,10 RAs) 2 G&As Incorporated mid-2001 - Located at Biocitech Parc, Paris (France) EUR 10.2M (USD 13M) raised since 2002 - Investors: BioAm, Axa PE, Auriga, Credit Agricole PE.

MUTABILIS’ research objectives Discovery of innovative anti-virulence treatments for nosocomial infections Therapeutic molecules : Inhibition of virulence factors. Therapeutic vaccines and antibodies

Background: Medical need for new anti-infective therapies Nosocomial infections (NI) occur in 2-10% of hospitalized patients (ICU, Surgery, internal medicine…) Three types of pathogens: Gram+ bacteria: 45%. Gram- bacteria: 35%. Others: 20%. Complications of nosocomial infections generate extensive hospitalization, and intensive care costs. Severe infections and sepsis can be lethal (30% cases) The increasing number of invasive procedures and the emergence of antibiotic resistance are causing a real public health problem Antibiotics-based treatments result in the destruction of commensal bacteria and drug resistance Newer antibiotics are kept as last resort therapy

Pathogenic bacteria use a range of virulence factors to establish infection Host defenses Virulence mechanisms Colonization Innate Immunity Specific Immunity Invasion Pathogenic bacteria Toxins Shield to immune system Environment adaptation

MUTABILIS’ approach to virulence Gut Blood Selective inhibition of the virulence factors required for systemic dissemination in the host. Systemic infection

Scientific strategy: Drug approach: Vaccine approach: Selective inhibition of pathogenic bacteria by targeting virulence factors necessary for bacterial spreading in blood Virulence inhibitors do not perturb development of commensal bacteria Diminished risk of developing resistant mutants because of lower selective pressure This lead to the discovery of new classes of antibacterial molecules that are not classical antibiotics Vaccine approach: Inhibition of specific pathogens in a bacterial species Preventive vaccine/passive immunity for nosocomial infections

THERAPEUTIC APPROACH: Antibiotics versus virulence inhibitors Common ground in both approaches: Infections are treated through eradication of bacteria in the blood. Advantages of virulence inhibitors: Virulence inhibitors do not perturb development of commensal bacteria. Diminished risk of developing resistant mutants because of lower selective pressure.

Anti-virulence product profile opens preventive therapy Anti-infective agent (not an antibiotic) which eradicates bacteria from the blood and leaves the commensal flora untouched. Product characteristics: No induction of bacterial resistance. No cross resistance with existing antibiotics. Large gram- spectrum. Large gram+ spectrum. Gram- and gram+ combination. Product positioning: Preventive therapy: compound will be used on its own.

Virulence inhibition: plan Mutagenesis of every coding sequence in the genome of a model bacteria. Identification of pathogen genes which are essential for producing systemic infection. Validation of these genes as therapeutic targets in experimental models of infection. Drug development based on molecules which inhibit these targets.

Drug discovery Objective: Discovery of new class of antibacterial molecules for selective inhibition of pathogenic bacteria Discovery process: Target identification (complete Tn mutagenesis of pathogenic Gram+ and Gram- pathogenic bacteria) and validation (KO mutants phenotype, protein function, consevation…) Rational drug design, virtual screening, hit identification

Anti-virulence product profile opens preventive therapy markets. VACCINATION ANTIVIRULENCE ANTIBIOTICS Pathogenic strains Prevention Broad spectrum therapy Specific to the risk of infection Infected patients Healthy individuals Patients at risk of infections Transplantees (kidney, bone marrow, liver, etc.) Intensive care patients Cancer patients undergoing treatment Kidney failure Corticoid treatment Haemophilus Meningococcus Pneumococcus E. Coli Streptococcus B

Conclusions: virulence projects MUTABILIS targets: conserved, required for virulence and systemic infection but not for commensalism. MUTABILIS developed assays needed for pharmacological studies. Efficacy prediction through animal model: targets functions are conserved in animal species and man. MUTABILIS using rational approaches did identify inhibitors molecules.

Research area of interest: Comparative genomics + physiopathology of infectious diseases Interactions bacteria/host Metabolic pathways common to pathogenic bacteria conserved targets Bacterial membranes and pharmacology : why some drugs get through or not?