1. A new antivirulence approach against pathogenic bacteria
dr shabeel pn

2. 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 Located at Biocitech Parc, Paris (France)
EUR 10.2M (USD 13M) raised since Investors: BioAm, Axa PE, Auriga, Credit Agricole PE.

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

4. 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

5. 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

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

7. 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

8. 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.

9. 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.

10. 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.

11. 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

12. 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

13. 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.

14. 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?