MICROBIOTIX A product-focused, small molecule, anti-infective company Terry Bowlin, Ph.D., CEO Donald Moir, Ph.D., CSO Norton Peet, Ph.D., Director of.

MICROBIOTIX

A product-focused, small molecule, anti-infective company

Terry Bowlin, Ph.D., CEODonald Moir, Ph.D., CSONorton Peet, Ph.D., Director of ChemistryMichelle Butler, Ph.D., Sr. ScientistMary Kittredge, Accounts Manager

CONFIDENTIALOctober 2006

October 2006

MICROBIOTIX STRATEGY

To discover and develop small

molecule anti-infective drugs which

inhibit novel bacterial targets

October 2006

Corporate Overview

• Launched in January 2000 and currently occupies 8,200 square feet of fully equipped laboratory and office space in Worcester, Massachusetts

• Core antibiotics technology based on scientific founders’ research at U Mass on inhibition of bacterial DNA replication

• Proprietary antibiotic discovery platforms targeting specific validated steps in drug resistant bacteria

• Current preclinical pipeline of novel bacterial DNA polymerase inhibitors (MBX500) and anti-herpes (CMV, HHV6, HHV8) inhibitor (MBX400)

• Target identification, validation and screening ongoing for novel antibacterials and biofilm inhibitors

• Active biodefense program for novel antibiotics

October 2006

MICROBIOTIX PIPELINE

COMPOUND INDICATION STATUS

MBX 500 Gram+ antibacterial Preclinical

MBX 400 Herpes (CMV, HHV6&8) Preclinical

MBX 1066 Broad Spectrum antibiotics for biodefense

Lead/SAR

MSL-049293 Biofilm Inhibitor Chemical Hits

- B. anthracis/S. aureus Screening

October 2006

ANTIBIOTIC DTRA PROJECT

PROPOSAL OVERVIEW - T. BOWLIN

PROJECT/MICROBIOLOGY - M. BUTLER

PROJECT/MECHANISM - D. MOIR

PROJECT/CHEMISTRY - N. PEET

PROJECT/MILESTONES/TIMELINES - T. BOWLIN

October 2006

PROJECT OBJECTIVES

The broad long-term objective of this project is to develop a new chemical class of therapeutic agents, the bis-(imidazolinylindole) series discovered in preliminary studies, for use against intracellular bacterial BW threats.

October 2006

PROJECT RATIONALE

Development of new chemical classes of broad-acting anti-bacterials is crucial for biodefense:

Likely to be potent on strains/species which are resistant to current drugs

Potential for acting on new pathways or targets within the microbial cell

Supplement and complement existing classes of antibacterials

October 2006

PROJECT STRATEGY

Our strategy is to:

Demonstrate in vivo efficacy of members of this bis-(imidazolinylindole) family of compounds by using animal models of B. mallei, B. pseudomallei, Y. pestis, F. tularensis and C. burnetii infection

Determine the mechanism of action of these compounds

Delineate the key structural features important for activity and provide back-up compounds

Conduct IND-enabling pharmacokinetic, toxicology and safety pharmacology studies

October 2006

Donald T. Moir, Ph.D.CSO, Microbiotix, Inc.Biology & Chemistry

Michelle Butler, Ph.D.Senior ScientistMicrobiotix, Inc.

In Vitro Microbiology

Donald Woods, Ph.D.Professor

University of CalgaryAnimal Models

Sina Bavari, Ph.D.Chief, Immunology

USAMRIIDAnimal Models

Norton Peet, Ph.D.Director of Chemistry

Microbiotix, Inc.Chemistry

Terry L. Bowlin Ph.D.CEO, Microbiotix, Inc.

Team Lead&

Preclinical IND enabling studies To be hired, Ph.D.

Regulatory ComplianceTo be hired, Ph.D.Clinical Director

Management Chart

October 2006

AIMS

Aim 1. Demonstrate potent, selective inhibitory activity of one or more bis-(imidazolinylindole) compounds in animal models of infection (year 1). Milestone: Identify an inhibitor exhibiting in vivo efficacy (ED50<30 mg/kg) against >2 category A or B

pathogens and minimum toxicity (MTD>300 mg/kg).

Aim 2. Establish the mechanism of action of the bis-(imidazolinylindole) class of compounds (year 1).

Aim 3. Demonstrate structure-activity relationships for the potency and selectivity of the bis-(imidazolinylindole) class of compounds (year 1-2). Aim 4. Conduct IND-enabling pharmacokinetic, toxicology and safety pharmacology studies (year 2). Aim 5. Prepare and file an IND application for a broad spectrum anti-bacterial active against intracellular BW threats (end of year 2).

October 2006

Aim 1 in vitro Studies

Preliminary Data

MIC assays with the following category A/B pathogens

Yersinia pestis

Burkholderia mallei

Burkholderia pseudomallei

Francisella tularensis

Intracellular assays for the obligate intracellular pathogen, Coxiella burnetii

October 2006

A HTS Assay for Growth Inhibition of Bacillus anthracis Yielded Four Potent Antibacterial Agents

B. anthracis (Sterne), expressing GFP as a marker for growth, was screened using the NCI open repository

The four most potent compounds displayed a dose-dependent inhibition of growth

FIG. 1. Dose Dependence of Inhibition

October 2006

Preliminary MICs—Gram-positive

MIC (g/mL)

Strain NSC-317880 NSC-317881 NSC-330867 NSC-369718Bacillus anthracis Ames 0.584 0.32 1.103 1.392B. anthracis Ames, ciproR 0.584 1.292 1.103 0.200B. anthracis 1024 1.168 0.162 0.551 0.348B. anthracis vollum 0.584 0.324 0.551 0.348B. brevis 0.584 0.646 0.276 0.174B. lichenformis 2.335 0.646 2.206 1.392B. megaterium 0.584 0.323 0.551 0.348B. pumilus 0.146 0.021 0.138 0.348B. subtilis 0.292 0.162 0.551 0.348Staphylococcus aureus 1.168 0.323 1.10 0.696Methicillin resistant S. aureus 2.335 0.250 2.2 2.785Enterococcus faecalis 0.584 0.162 2.205 0.696Vancomycin resistant E. faecalis ND 0.150 ND NDVancomycin resistant E. faecium ND 0.150 ND ND

October 2006

Preliminary MICs—Gram-negative

MIC (g/mL)

Strain NSC-317880 NSC-317881 NSC-330867 NSC-369718Escherichia coli 0.584 0.646 1.10 1.392Klebsiella pneumoniae >18.68 10.34 >17.64 5.57Pseudomonas aeruginosa PAO1 1.168 0.323 17.64 1.392Yersinia pestis 18.68 20.68 8.82 1.392Burkholderia mallei 9.34 10.34 8.82 11.14B. pseudomallei 18.68 >20.68 >17.64 2.784B. thailandensis 18.68 20.68 17.64 2.784B. cepacia 18.68 >20.68 4.41 22.28

October 2006

Preliminary MBCs—B. anthracis

MBC, g/mL (MBC/MIC ratio)

Strain NSC-317880 NSC-317881 NSC-330867 NSC-369718B. anthracis Ames, ciproR 1.168 (2) 1.292 (1) 4.41 (4) 0.348 (2)B. anthracis 1024 2.336 (2) 0.646 (4) 2.206 (4) 0.696 (2)B. anthracis vollum 1.168 (2) 0.162 (1) 1.103 (2) 0.348 (1)Bacillus anthracis Ames spores (germinated)

0.146 (ND) 0.162 (ND) 0.276 (ND) 0.174 (ND)

October 2006

Compounds Inhibit B. anthracis as an Intracellular Pathogen Within Macrophages

Macrophage cells were infected with B. anthracis (Sterne strain) and simultaneously treated with the compounds or a DMSO control

Measurements of cell viability were by SYTOX Green exclusion with analysis by flow cytometry

After 4 hours, the NCI compounds protected the cells from B. anthracis-mediated death

Compounds were also non-toxic to the cells

SYTOX Green measurements of macrophage viabilityacrophage viability

October 2006

Antibacterial Activity of NSC-317881 (Resynthesis) Compared to Previously Presented Activity Against Gram-positive Strains

MBX Strain MIC (g/mL)MBX USAMRIID Strain MIC (g/mL)

USAMRIID

Bacillus subtilis (BD54) 0.039 No designation 0.162B. cereus (ATCC 4342) 0.039

B. thuringiensis (ATCC 10792) 0.156

B. anthracis (Sterne) 0.078 B. anthracis 1024 0.162B. anthracis (Ames ANR) 0.156 Ames 0.323B. megaterium (ATCC 12872) 0.039 Clinical 0.323B. lichenformis (ATCC 14580) 0.078 Clinical 0.646Staphylococcus aureus (ATCC 25923) 0.078 No designation 0.323S. aureus (Smith, ATCC 13709) 0.059 No designation 0.323MRSA (clinical 1094) 0.156 Clinical 0.250Enterococcus faecalis (ATCC 29212) 0.156 Clinical 0.162VRE faecalis (ATCC 51575) 0.068 No designation 0.150E. faecium (ATCC 19434) 0.156

VRE faecium (clinical B42762) 0.195 No designation 0.150

NH

NH

N

NH HN

N

•2TFA

October 2006

Antibacterial Activity of NSC-317881 (Resynthesis) Compared to Previously Presented Activity Against Gram-negative Strains

MBX Strain MIC (g/mL)MBX USAMRIID Strain MIC (g/mL)

USAMRIID

Escherichia coli (J53) 0.469 Clinical 0.646Klebsiella pneumoniae (clinical 5657) 3.75 Clinical 10.34Pseudomonas aeruginosa (PAO1) 5 PAO1 0.323P. aeruginosa (ATCC 27853) 4.38 PAO1 0.323Burkholderia thailandensis (E264) >80 Environmental 20.68Stenotrophomonas maltophilia (ATCC 13637) 0.156

NH

NH

N

NH HN

N

•2TFA

October 2006

Aim 1 in vivo Studies Preliminary mouse toxicity data Using the following animal models, we will assess the potencies of the NCI

compounds in vivo: F. tularensis—to be performed in the laboratory of Dr. Sina Bavari using the aerosol

route of administration of strain Schu4 in a mouse model of tularemia Y. pestis-- to be performed in the laboratory of Dr. Sina Bavari using the aerosol route

of administration of strain CO-92 in a mouse model of pneumonic plague C. burnetii-- to be performed in the laboratory of Dr. Sina Bavari using the

intraperitoneal route of administration of the Nine Mile 1 strain in a mouse model of Q fever

B. pseudomallei-- to be performed in the laboratory of Dr. Donald Woods using the intraperitoneal route of administration of the 1026b strain in a mouse model of meliodosis

B. mallei-- to be performed in the laboratory of Dr. Donald Woods using the intraperitoneal route of administration of the 1026b strain in a mouse model of glanders

Maximum tolerated dose (MTD) determinations in mice

October 2006

Toxicity Determination in Mice

Compound Dose (mg/kg) Route # Mice # Surviving on Day 5

NSC-317880 100 i.p. 6 6200 i.p. 6 6

400 i.p. 6 6

NSC-317881 100 i.p. 6 6200 i.p. 6 6

400 i.p. 6 6

NSC-330687 25 i.p. 6 650 i.p. 6 6

100 i.p. 12 11

200 i.p. 12 11

400 i.p. 6 2

NSC-369718 50 i.p. 6 6100 i.p. 6 6

200 i.p. 6 6

October 2006

AIMS

Aim 1. Demonstrate potent, selective inhibitory activity of one or more bis-(imidazolinylindole) compounds in animal models of infection (year 1).

Aim 2. Establish the mechanism of action of the bis-(imidazolinylindole) class of compounds (year 1). Milestone: Defined mechanism of action and target which are common to multiple bacterial BW species but distinctly different in mammalian cells.

Aim 3. Demonstrate structure-activity relationships for the potency and selectivity of the bis-(imidazolinylindole) class of compounds (year 1-2).

Aim 4. Conduct IND-enabling pharmacokinetic, toxicology and safety pharmacology studies (year 2). Aim 5. Prepare and file an IND application for a broad spectrum anti-bacterial active against intracellular BW threats (end of year 2).

October 2006

NSC 317880, NSC 317881, NSC 330687, NSC 369718 & New analogs

1. Macromolecular Synthesis Assays & cidal/static determination(DNA, RNA, protein, cell wall, & lipid biosynthesis)

2. Cell Membrane Integrity Assays-- Fluorescent dye retention – membrane potential

-- Erythrocyte hemolysis – membrane lysis

3.a. Genes Up-Regulated in Resistant Strains-- Identify over-expressed E. coli genes which confer resistance

3.b. Mapping Mutations to Resistance-- Select resistant mutants; then,

-- Transfer resistance with a genomic plasmid library, or-- co-transduce Tn markers and compound resistance

4. Expression Profiling-- Identify genes or patterns of genes up- or down-

regulated in response to treatment with compound

5. Target Confirmation -- Demonstrate MIC alterations in response to up- or down-

regulation of the putative target-- Demonstrate plasmid-mediated transfer of resistance in

>1 species

Inhibits 0 or 1 pathwayInhibits >1 pathway

YesNo

Aim 2 – Mechanism of Action

Membrane is target

October 2006

Aim 2 – Mechanism of Action:Macromolecular Synthesis Assays

Example: Specificity of a Fatty Acid Synthesis Inhibitor in MMS Assay

N. Kaplan et al., 46th ICAAC, 2006

October 2006

Example: MBX-500 is Bactericidal Against Enterococcus faeciumEnterococcus faecium Time Kill Assay

0

2

4

6

8

10

0 5 10 15 20 25

Time (hours)

Lo

g C

FU

/mL Control

Vanco-4xMIC

MBX-500-8x MIC

MBX-500-4x MIC

MBX-500-2x MIC

Only 3 bactericidal mechanisms are known:Only 3 bactericidal mechanisms are known:(a)(a) membrane integrity damagemembrane integrity damage(b)(b) DNA damageDNA damage(c)(c) prevention of cell division or segregation of DNA into daughter cellsprevention of cell division or segregation of DNA into daughter cells

Aim 2 – Mechanism of Action:Bactericidal/Bacteristatic Determination

October 2006

+++

+

++ + +

+

+

+

-- ---

--

---

Membrane potential direction

+++

+

++ + +

+

+

+

-- ---

--

---

Add cells

Add drug

If drug affects membrane potential

If drug does not affect membrane potential

Fluorescence increase No fluorescence

Fluorescence

Concentrated in cells --Fluorescence quenched

DiSC3(5)

NH

NH

N

NH HN

N

•2TFA

Aim 2 – Mechanism of Action:Assay for Effect on Membrane Potential

October 2006

yfgPyfg

MIC = 8 MIC > 8

gene

mRNA

protein

gene

mRNA

protein

yfgPyfg

Preg yfg

plasmid

Aim 2 – Mechanism of Action:Target Identification by Over-expression Rescue

October 2006

Rescuing library of 500 over-expressing clones Non- rescuing libraries

0.5X MIC + + +

+

+

+

1.0X MIC

2.0X MIC

An

tib

ioti

c co

nce

ntr

atio

n

Each OER library contains ~500 genes“+” Indicates bacterial growth

Aim 2 – Mechanism of Action:Target Identification by Over-expression Rescue

October 2006

Select resistant mutants

Identify genetic locus conferring resistance

Linkage to transposon in a random Tn library (co-transduction)

Linkage to plasmid in a cloned genomic library (co-transformation)

Sequence plasmid insert DNA and/or Tn-linked DNA to identify locus by

match to database sequence

Aim 2 – Mechanism of Action:Mapping Mutations to Resistance

October 2006

Stress Response&

“pumps”

Rps & Rpl Loci

Biosynthetic Locus

Ampicillin

Cycloserine

Vancomycin

Stationary

Control

Phosphomycin

Erythromycin

Tim

eAim 2 – Mechanism of Action:

Expression Profiling

October 2006

AIMS

Aim 1. Demonstrate potent, selective inhibitory activity of one or more bis-(imidazolinylindole) compounds in animal models of infection (year 1).

Aim 2. Establish the mechanism of action of the bis-(imidazolinylindole) class of compounds (year 1).

Aim 3. Demonstrate structure-activity relationships for the potency and selectivity of the bis-(imidazolinylindole) class of compounds (year 1-2). Milestone: Identify key structural features for potency and selectivity; provide back-up compounds with MIC in serum <1 µg/ml with a selectivity index (CC50/MIC) >100.

Aim 4. Conduct IND-enabling pharmacokinetic, toxicology and safety pharmacology studies (year 2).

Aim 5. Prepare and file an IND application for a broad spectrum anti-bacterial active against intracellular BW threats (end of year 2).

October 2006

PROGRESS/CHEMISTRY

Preliminary Data Successful synthesis of NSC 317,881 In progress: NSC 317,880 Proposed route to NSC 330,687 Proposed route to NSC 369,718 Future SAR directions

October 2006

AIM 3 – TARGET COMPOUNDS

NSC # Structure MW cLogP HBA HBD RDF

NSC-317,880 394 5.82 6 4 4

NSC-317,881 445 7.32 6 4 4

NSC-369,718 485 7.88 7 4 4

NSC-330,687 368 5.22 6 4 3NH N

H

N

NHHN

N

NH N

HO N

H

NN

NH

NH

N

NH

NH

N

HN

NH

N

NH NH

N

HN

October 2006

Overlay of NSC Compounds

Overlay of NSC Compounds: NSC 317,880 (yellow), 317,881 (white), 369,718 (red), 330,687 (blue).

October 2006

Madelung Route to NSC 317,881

NC NC NO2 NC NH2

NC NH

O

HN

O

CNNH

NC NH

CN

NH

NH

HN

NN

NH

HNO3

H2SO4

H2 Pd/C

MeOH

terephthaloyl chloridepyridineCH2Cl2

BuLi or LDA

THF or THF/hex

H2NNH2 P2O5

120 °C

NSC-317,881

October 2006

Sonogashira Route to NSC 317,881

NC

Br

NC

Br

NO2 NC

Br

NH2

NO2 O2N

CNNC

NH2 H2N

CNNC

NHNC N

H CN

HNO3

H2SO4

SnCl2

HCl (aq.)

Pd(PPh3)Cl2DMF

Pd(PPh3)Cl2DMF

Pd(PPh3)Cl2DMF120 °C

SnCl2

October 2006

Successful Synthesis of NSC 317,881

NSC 317,881

NO2NC NO2NC

O2N CN

NH

NC NH

CNNH

NH

HN

NN

NH

NC

CHO

OHCHNO3

H2SO4 piperidinesulfolane150 °C

P(OEt)3120 °C

H2NNH2

P2S5120 °C

October 2006

Proposed Synthesis of NSC 317,880

NSC 317,880

NC NC

O

OEt

O

NO2NO2

NH

COOEt

NC

NH

CH2OH

NCNH

CH2Br

NC

NH

CHO

NCNHNC PPh3

Br-

+NHNC

NH CN

diethyl oxalate

NaOEtEtOH

Zn dust

THF

LiBH4THFreflux

NH N

H

N

NHHN

N

+

Swern

PBr3

CH2Cl2

PPh3THFreflux

NaH

THF

H2NNH2 P2S5

120 °C

October 2006

Proposed Synthesis of NSC 330,687

NSC 330,687

COOH

OHC

CN

OHC

CN

NO2NC

NO2

CN

OHC NO2

NHNC

NH

CN

NH N

HHN

NN

NH

NC NO2

1) NH4OH

2) PPE

HNO3

H2SO4

piperidinesulfolane150 °C

P(OEt)3

120 °C

H2NNH2 P2S5

120 °C

October 2006

Proposed Synthesis of NSC 369,718

OCN

Br

NHBr

NC NO2 NC NO2

NMe2

NHNC

NO2Br NO2Br

NMe2

Br

OH

CHO Br CHO

OCH2CN

DMFDMA

piperidine

H2 Pd/C

MeOH

DMFDMA

piperidine

H2 Pd/C

MeOH

NaHBrCH2CN

THF

LDA

THF

October 2006

Proposed Synthesis of NSC 369,718

NSC 369,718

NH

NC

BNH

NC NHNC

NH

NHNC

NH

B

NH

NCNH

OCN

NH N

HO N

H

NN

NH

O

OB2Pin2

catalyst

O

O

Pd(OAc)2K2CO3

propanol

B2Pin2catalyst

Pd(OAc)2K2CO3

propanol

H2NNH2 P2S5

120 °C

NH

Br

OCN

Br

October 2006

Retrosynthesis: Many Possibilities

NH

NC

Ar

NC NH

Ar

O

MadelungNC NH

N Ar

Fisher

NH2NC

Ar

CHO

NH

Ar

O

NC NC NO2

Ar

Cadogan-Sundberg

NH2

Ar

ONC

NC Br

Ar

Sonogashira

intramolecularHeck

NC NH

Ar

Br

Barluenga

Fürstner

Buchwald

October 2006

Initial Pharmacophore

NH

N

NH

indole,benzoxazole

HN

N

NH

NH

NH

NH

O

head-to-tailhead-to-head

October 2006

Possible Future Directions

NH

N

NH R

NH

N

NH

R

NHN

NH

NH N

NH

NH

N

NH

HN

O

R

NHN

NH

N

N

NH N

NH

NH

N

N

NH

NH

N

N

NH

Symmetrical Analogs Truncated Analogs

October 2006

AIMS

Aim 1. Demonstrate potent, selective inhibitory activity of one or more bis-(imidazolinylindole) compounds in animal models of infection (year 1).

Aim 2. Establish the mechanism of action of the bis-(imidazolinylindole) class of compounds (year 1).

Aim 3. Demonstrate structure-activity relationships for the potency and selectivity of the bis-(imidazolinylindole) class of compounds (year 1-2).

Aim 4. Conduct IND-enabling pharmacokinetic, toxicology and safety pharmacology studies (year 2). Milestone: Complete two species GLP toxicology & safety pharmacology studies for the optimal bis-(imidazolinylindole) compound suitable for IND submission.

Aim 5. Prepare and file an IND application for a broad spectrum anti-bacterial active against intracellular BW threats (end of year 2).

October 2006

IND ENABLING STUDIES

Toxicology: 2 species acute and multiple dose GLP toxicology studies will be performed in rats and dogs

Safety pharmacology: Identify any undesirable preclinical pharmacodynamic properties relevant to human safety

Pharmacokinetics and Bioavailability: The intent is to fully understand the absorption, distribution, metabolism and excretion (ADME) of our lead compound

October 2006

AIMS

Aim 1. Demonstrate potent, selective inhibitory activity of one or more bis-(imidazolinylindole) compounds in animal models of infection (year 1).

Aim 2. Establish the mechanism of action of the bis-(imidazolinylindole) class of compounds (year 1). Aim 3. Demonstrate structure-activity relationships for the potency and selectivity of the bis-(imidazolinylindole) class of compounds (year 1-2).

Aim 4. Conduct IND-enabling pharmacokinetic, toxicology and safety pharmacology studies (year 2).

Aim 5. Prepare and file an IND application for a broad spectrum anti-bacterial active against intracellular BW threats (end of year 2). Milestone: IND approval for clinical Phase I human safety evaluation. 

October 2006

IND Filing

Hire regulatory and clinical manager

Conduct pre-IND meeting with FDA

Overall 2 year project milestone: IND approval for clinical phase I human safety evaluation

October 2006

Timeline Year 1 Year 2 Task 1Q 2Q 3Q 4Q 1Q 2Q 3Q 4Q 4.1 Efficacy 4.1.1 Small Scale Synthesis 4.1.2 Large Scale Process 4.1.3 In vitro potency 4.1.4 In vivo potency 4.1.4.1 F. tularensis 4.1.4.2 Y. pestis 4.1.4.3 C. burnetii 4.1.4.4 B. pseudomallei 4.1.4.5 B. mallei 4.1.5 Murine toxicity Milestone: Identify a Lead Compound

4.2 Mechanism of Action 4.2.1 Macromolecular Synthesis 4.2.2 Membrane Perturbation 4.2.3 Map Loci 4.2.4 Genetic Expression Profile 4.2.5 Hypersensitivity and Resistance

Milestone: Defined MOA

October 2006

Timeline (cont.)

Year 1 Year 2 Task 1Q 2Q 3Q 4Q 1Q 2Q 3Q 4Q 4.3 SAR 4.3.1 Molecular Modeling 4.3.2 Synthesis of Analogs 4.3.2.1 NSC 317,880 4.3.2.2 NSC 317,881 4.3.2.3 NSC 330,687 4.3.3 Biological Evaluation 4.3.3.1 Potency 4.3.3.2 Cytotoxicity 4.3.3.3 Kinetics 4.3.3.4 Frequency of Resistance 4.3.3.5 Bioavailability (in vitro) 4.3.3.6 Drug Interactions 4.3.3.7 Metabolic Stability 4.3.3.8 QT Interval Milestone: Backup Compounds Identified

October 2006

Timeline (cont.)

Year 1 Year 2 Task 1Q 2Q 3Q 4Q 1Q 2Q 3Q 4Q 4.4 IND-Enabling Studies 4.4.1 PK and Bioavailability 4.4.2 Toxicology Studies 4.4.2.1 Rat 4.4.2.2 Dog 4.4.2.3 Genetic 4.4.3 Safety Pharmacology Milestone: 2 spec. Tox & Safety Profile

October 2006

Timeline (cont.)

Year 1 Year 2 Task 1Q 2Q 3Q 4Q 1Q 2Q 3Q 4Q 4.5 Prepare and File IND 4.5.1 Hire Regulatory Manager 4.5.2 Project Reports 4.5.3 Hire Clinical Director 4.5.4 Clinical Protocols 4.5.5 FDA Pre-meeting 4.5.6 File IND Milestone: IND Approval

October 2006

Research Progression

Aim 1. Demonstrate potent, selective

inhibitory activity of one or more bis-

(imidazolinylindole)

Aim 2. Establish the mechanism of action of

the bis-(imidazolinylindole) class

of compounds

Aim 4. Conduct IND-enabling pharmacokinetic, toxicology and safety

pharmacology studies

Milestone 1: ED50<30mg/kg

against >2 category A or B pathogens MTB

>300 mg/kg

Milestone 2: Defined MOA and target common to

multiple species

Aim 3. Demonstrate structure-activity relationships for the potency and selectivity of bis-(imidazolinylindole) class of compounds

Aim 5. Prepare and file IND application for a broad-spectrum antibacterial active against

intracellular biowarfare agents

Milestone 4: 2-species GLP tox. And safety pharmacology Milestone 3: ID key structural features,

backup compounds with MIC<1 µg/ml, selectivity index (CC50/MIC) > 100

Milestone 5: IND approval for clinical Phase I human safety evaluation

Year 1

Year 2

October 2006

Key Advantages of Microbiotix Approach

The team believes that there are several competitive advantages in its approach to the development of new therapy for biodefense. These advantages include the following:

Identification of a novel series of broadly acting antibiotics active against multiple bioterrorism category A and B intracellular pathogens.

Involvement of an impressive group of collaborators to carry out BSL level 3/4 development and help guide the project.

MBX has a proven track record in antibacterial drug discovery and development.

The team has extensive scientific expertise in bacterial genomics and genetics.

MBX management and team leadership has a long term track record in successfully developing drugs and obtaining regulatory approval.