Gram-negative bacteria causing serious and often deadly infections
Enterobacteriaceae are a family of Gram-negative bacteria responsible for a significant fraction of cases across conditions, including complicated urinary tract infections, bloodstream infections and hospital-acquired pneumonias.
We estimate there are more than one million infections in the US annually caused by Enterobacteriaceae across these three settings. Enterobacteriaceae are facing growing numbers of antibiotic resistant strains. Two of the most alarming antibiotic resistance trends, which make the CDC list of urgent and serious threats are:
- Extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae. ESBL is an enzyme that allows bacteria to become resistant to a wide variety of penicillin and cephalosporin antibiotics.
ESBL-producing Enterobacteriaceae account for an estimated 26,000 infections annually in the US with 1,700 deaths, according to the CDC.
- Carbapenem-resistant Enterobacteriaceae (CRE). CRE are resistant to nearly all existing antibiotics, including carbapenems which are considered the antibiotics of last resort. CRE account for an estimated 9,000 infections per year in the US and 600 deaths, according to the CDC.
We have discovered a series of new mechanism antibiotics targeting Enterobacteriaceae, called DDS-04.
Our DDS-04 series acts via LolCDE, a novel bacterial target. The LolCDE site of DDS-04 series activity is conserved in the majority of therapeutically important Enterobacteriaceae, resulting in targeted spectrum compounds. With its new mechanism of action, the DDS-04 series was rapidly bactericidal and highly potent across globally diverse Enterobacteriaceae strains in research studies, which included multi-drug resistant isolates. Importantly, the DDS-04 series also showed low propensity for resistance development and did not show cross-resistance with existing classes of antibiotics, suggesting that DDS-04 compounds have the potential to overcome known resistance mechanisms. This profile makes the DDS-04 series attractive for further development for the treatment of Enterobacteriaceae infections.
Our DDS-04 series compounds cured infection in a translationally-relevant animal model of urinary tract infection, one of the major sites for Enterobacteriaceae infection. Therapeutic concentrations of the DDS-04 compound were also observed in other major sites in the animal model where life-threatening Enterobacteriaceae infections occur, including the lungs and the bloodstream.
Our initial pre-clinical candidate from the DDS-04 series is SMT-738.
There is a clear and urgent need to develop new mechanism antibiotics to treat infections caused by Enterobacteriaceae, especially given increasing issues of resistance to existing agents. We are developing the DDS-04 series as a potential Enterobacteriaceae drug of choice, which could address several body sites of infection.
We see potential to develop an Enterobacteriaceae-targeted compound in a number of body system settings where Enterobacteriaceae cause serious infections and where current therapies do not provide for confidence in treatment because of growing resistance issues.
Latest Research Publications
Enterobacteriaceae / 25 Apr 2022
SMT-738: A Novel Small-Molecule Inhibitor of Bacterial Lipoprotein Targeting Enterobacteriaceae
E. Breidenstein ECCMID 2022
Enterobacteriaceae / 05 Sep 2019
In vivo Proof of Concept for a Novel Small Molecule Inhibitor of Bacterial Lipoprotein Transport Targeting Enterobacteriaceae
E. Breidenstein ASM/ESCMID 2019
Enterobacteriaceae / 14 Apr 2019
Novel Small-Molecule Inhibitors of Bacterial Lipoprotein Transport with Potent Antimicrobial Activity Against Enterobacteriaceae
E. Breidenstein ECCMID 2019