Therapy Analysis - Antibiotic-resistance: fighting the superbugs
New beginnings
In response to the challenge of antibiotic resistance, pharmaceutical companies continue to develop novel antimicrobials which may lead to a new generation of drugs for the treatment of such infections. While many 'traditional' antibiotics act by disrupting cell wall synthesis, today pharmaceutical companies are employing various novel mechanisms of action in order to combat these resistant bacteria (Graph 2) by targeting the very protein the bacteria are mutating. Indeed, several early stage compounds are currently in development for antibiotic-resistant infections (Graph 1). S Korean pharmaceutical company Dong-A Pharma is developing DA-7218, the lead in a series of orally-available oxazolidinone drugs for the treatment of Gram positive infections. It is currently in a US multiple ascending-dose Phase I study in patients with Gram positive infections, including MRSA, to assess safety, tolerability and pharmacokinetics. Previous studies have shown potential for daily dosing with DA-7218. Dependent on further development, approval is expected in 2013.
Several preclinical compounds are also showing early promise. Merck & Co's platencin, a natural product and dual inhibitor or FabH and FabF, has shown potent activity in preclinical studies, with no toxicity observed. Platencin does not show cross-reactivity to antibiotic-resistant strains such as MRSA and VRE. Also in preclinical development is Replidyne's diaryldiamine anti-infective, REP-3123, indicated for the treatment of antibiotic-resistant C. diff infections. A hamster model has previously shown REP-3123 to be superior to vancomycin. It also inhibited moxiflaxacin- and clindamycinresistant strains of C. diff. Replidyne expects to file an IND in the second half of 2008.
Phynova is developing PYN-6. Currently in preclinical studies, PYN-6 has shown activity against MRSA and vancomycin- and teicoplanin-resistant bacteria. Phase I trials are planned for 2008, with Phynova seeking to out-license PYN-6 after completion of Phase II development.
