1. CMV-related infections in transplant recipients
Potent/novel nucleoside analog dual DNA polymerase/kinase inhibitor
Phase 1 completed
CMV, a member of the herpesvirus family, is benignly present in the majority of adults, where the immune system is able to prevent it from causing disease. However, CMV infection continues to be a major cause of morbidity and mortality in immunosuppressed patients, especially recipients of solid organ or bone marrow transplants. There are 126,670 solid organ transplant operations performed every year worldwide (2015 Global Observatory on Donation & Transplantation), with over 33,000 (Organ Procurement and Transplantation Network National Data, 2017) of these in the United States.
Our goal is to develop a safer and more effective therapy to protect vulnerable
patients from this life-threatening infection.
MBX-400 (filociclovir):
Unique dual mechanism-of-action (DNA polymerase and UL97 kinase)
> 5x more potent than the current gold standard therapy (Valcyte®)
Active against resistant isolates
No genotoxicity
MBX-400 has completed Phase 1 studies
2. Adenoviral conjunctivitis
Potent antiviral activity against adenovirus
Preclinical development
Adenoviruses are non-enveloped, double-stranded DNA viruses which affect multiple human tissues. It is the most common cause of infectious conjunctivitis worldwide. There are four major types of ophthalmic adenovirus infection: epidemic keratoconjunctivitis, pharyngoconjunctival fever, follicular conjunctivitis and acute hemorrhagic conjunctivitis. Hospitals, long term care facilities, ophthalmology clinics, schools, daycare centers and community pools are primary locations for adenoviral conjunctivitis to be contracted, with rapid spread of the infection. Absence of any current therapy results in palliative approaches as standard of care, resulting in increased risk for long term sequelae and loss of sight. Half of viral conjunctivitis cases are misdiagnosed as bacterial conjunctivitis, with an average of 2.4 visits to physician offices per case annually.
Our goal is to develop a first-in-class, highly differentiated product for ubiquitous, highly contagious ophthalmic viral infections that can cause long term negative sequelae.
MBX-400 (filociclovir):
Potent inhibitor of adenovirus in vitro and in vivo
Broad-spectrum efficacy against other viruses (CMV, VZV, EBV) that cause eye disease
Broad efficacy against multiple adenoviral serotypes
Potential to be the first approved antiviral targeting adenovirus
MDR Programs
Our goal: the identification and development of innovative treatments for priority
multi-drug resistant bacterial pathogens identified by the CDC and WHO
“Antimicrobial resistance poses a catastrophic threat. If we don’t act now, any one of us
could go into hospital in 20 years for minor surgery and die because of an ordinary
infection that can’t be treated by antibiotics. And routine operations like hip
replacements or organ transplants could be deadly because of the risk of infection… We
need to encourage more innovation in the development of antibiotics – over the
past two decades there has been a discovery void around antibiotics, meaning diseases
have evolved faster than the drugs to treat them.”
(Reproduced with kind permission from Drug Discovery World Summer 2017 Vol. 18 No.3 Pages 9-14.)
Discovery of novel antibiotics* is not keeping pace with the
emergence of new superbugs
*This chart excludes bedaquiline, which is the first drug in a new class to treat tuberculosis.
Source: Pew Charitable Trusts; Deak D, Powers JH, Outterson K, Kesselheim AS. Progress in
the Fight Against Multidrug Resistant Bacteria?: A Review of FDA Approved Antibiotics 2010-2015.
ANNALS OF INTERNAL MED. 2016 MAY 31. DOI: 10.7326/M16-0291.
Microbiotix MDR Programs
Two series of spectinomycin analogs – spectinamides and aminospectinomycins
STD + MDR/XDR TB
Novel analogs of known antibacterial class (G+/G-)
Preclinical
Novel analogs of the antibiotic spectinomycin, a member of the
aminoglycoside antibiotic family
Act via inhibition of protein synthesis binding to the 30S ribosome in a
site unique among protein synthesis inhibitors
Spectinamides
Novel semisynthetic spectinomycin analogs with narrow-spectrum
antitubercular activity have shown promise against multidrug-resistant (MDR)
and extensively drug-resistant (XDR) tuberculosis.
Demonstrated potent inhibition of MDR/XDR TB.
Excellent in vitro activity with no cross-resistance to other TB agents.
Demonstrated efficacy in multiple in vivo models of TB infection.
MDR/XDR TB
TB is an infectious disease caused by Mycobacterium tuberculosis and is
the leading cause of death worldwide from a single infectious agent. An estimated
1.7 billion people worldwide are infected with M. tuberculosis, 5-15% of whom
will go on to develop the disease within their lifetime. In 2016, there were over over 1.6
million TB deaths (WHO Global TB Report 2017). Multidrug-resistant TB (MDR-TB) is a
persistent threat, with 490,000 cases, and an additional 110,000 cases of rifampicin-resistant
TB (the most effective first line TB drug), in 2016.
Aminospectinomycins
Novel spectinomycin derivatives with improved potency against Gram-negative
and Gram-positive species, including drug-resistant clinical pathogens.
Demonstrated efficacy in multiple in vivo models.
Resistance – mutants arise at a very low frequency (10-11).
No cross-resistance against protein synthesis inhibitors.
Activity versus drug-resistant pathogens.
STD and biodefense pathogens
Drug-resistant Neisseria gonorrhoeae is classified as an Urgent Threat
Level pathogen by the CDC and as a High Priority Pathogen by the WHO. The
aminospectinomycins have also demonstrated activity against Chlamydia
trachomatis and the biodefense pathogens Burkholderia mallei,
Francisella tularensis and Bacillus anthracis.
Type III Secretion System (T3SS)
Ventilator-associated-pneumonia/CF/bacteremia
Pseudomonas aeruginosa virulence target
Lead Optimization
Microbiotix’s unique approach to targeting drug-resistant Gram-negative
bacteria focuses on bacterial virulence, specifically the type III secretion
system of Pseudomonas aeruginosa. The novel inhibitors, discovered by
Microbiotix scientists, have been shown to reverse the pathogen’s disruption
of the host innate immune response to infection and are not subject to
efflux or existing antibiotic resistance mechanisms.
During infection, this system secretes toxins that cause destruction
primarily of neutrophils and macrophages, disrupting the host’s immune
response, thus promoting the establishment and dissemination of infections.
Mechanism: Inhibition of type III secretion system (T3SS)
Needle type projection (PscF) delivers toxins into host cells,
destroying macrophages and neutrophils, thus disrupting the host’s immune response
T3SS inhibitors, targeting PscF, reverse this process, preventing
the establishment and dissemination of infection, while avoiding
efflux and existing resistance mechanisms
Prevention and treatment of ventilator-associated pneumonia (VAP) caused by P. aeruginosa
VAP is an urgent medical need.
Common infection in critically ill patients.
High mortality rates: >35% for MDR strains.
Elevated healthcare costs: ～ $40,000 per episode.
Novel anti-virulence approach.
Strong partnerships
Microbiotix was among the first recipients of funding ($3.2 million) from CARB-X (Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator).
Microbiotix and its development partner, the UK’s AMR Centre, have
combined resources and antimicrobial R&D expertise to accelerate the
development of Microbiotix’s lead bacterial anti-virulence candidate.
Trans-translation
Broad spectrum G+/G-
Unexploited MOA
Lead Optimization
Trans-translation is a novel antibacterial target
Bacterial translation is plagued by transcription errors, mRNA damage and
translational frameshifting events that result in non-stop ribosome
complexes, preventing release of protein products and inhibiting further
translation. Recovery of non-stop complexes is a crucial bacterial process
mediated primarily by trans-translation acting on a region of the bacterial
ribosome highly conserved across all sequenced bacterial genomes.
Trans-translation
Found in >99.9% of sequenced bacterial genomes
Occurs in an estimated >2% of all translation events
Requires rescue ~5 times/replication cycle
Rescue primarily mediated by trans-translation pathway
Essential in multiple pathogenic species including N. gonorrhoeae
Backup pathways not universal; often regulated by trans-translation
Trans-translation gene homologs are not found in metazoans
Trans-translation / Pathogens
We have demonstrated that our lead compounds inhibit non-stop ribosome rescue,
acting as potent antimicrobials against a range of pathogens, including MRSA
(and all other major CAP pathogens), Neisseria gonorrhoeae (among several
STD pathogens), M. tuberculosis, and Francisella tularensis (among other biodefense
targets). These compounds exhibit minimal toxicity towards mammalian cells,
excellent pharmacokinetics, oral bioavailability, tolerability and antibiotic
activity in multiple in vivo models.
Efflux pump inhibitors
Pathogenic Enterobacteriaceae
Potent activity vs RND efflux pumps
Lead Optimization
The rise of multidrug resistant (MDR) Gram-negative pathogens complicates our
ability to treat bacterial infections with antibiotics. MDR efflux pumps play a
major role in the acquisition and expression of the MDR phenotype. The major MDR
efflux pumps in the Gram-negative pathogens are the resistance-nodulation-division
(RND) superfamily pumps. Efflux pump inhibitors (EPIs) that target RND superfamily
pumps could play an important role in the clinic as adjunctive therapy to increase
antibiotic efficacy, decrease resistance and attenuate virulence in Gram-negative pathogens.
The RND family efflux pumps increase intrinsic resistance of Gram-negative
pathogens to antibacterial agents.
Overexpression of RND type efflux pumps leads to MDR.
Efflux pump inhibitors (EPIs) that target RND efflux pumps increase the
antibiotic susceptibility of MDR pathogens.
RND pumps are present in all Gram-negative pathogens.
We are developing efflux pump inhibitors for use as a combination therapy
with an FDA-approved antibiotic that will:
-Increase antibacterial potency at low concentrations
-Decrease frequency of resistance mutations.
We are optimizing a series of novel pyranopyridine EPIs that target RND-type efflux pumps
that exhibit potent activity against pathogens of the Enterobacteriaceae, favorable in vivo
pharmacokinetics, and efficacy in an in vivo infection model.
AcrAB-TolC: RND efflux pump
Carbapenem-resistant Enterobacteriaceae (CRE) is classified as an Urgent Threat Level pathogen by the CDC and as a Critical Priority Pathogen by the WHO.
CRE have become resistant to all or nearly all of today’s antibiotics.
Almost 50% of hospital patients that get CRE bloodstream infections die from the infection.
