At the recent “Superbugs and Superdrugs” conference in London, Nora Kaarela, CEO of Ipsat Therapies (www.ipsat-ther.com), commented, “Hospital-acquired bacterial infections are a leading cause of death in the U.S., and it costs between $16,000 and $100,000 per patient to treat this largely preventable problem.”
Despite the alarming rise in resistant bacteria, only a dozen or so new antibiotics have been approved by the FDA in the past ten years compared to double that number from 1988–1998, which begs the question: What’s behind the steady decline in numbers of new antibiotics coming to market?
Jeff Alder, Ph.D., senior director, global clinical development, at Bayer Healthcare (www.bayerhealthcare.com) observed, “A complex blend of properties is needed for an antibacterial drug, it is much tougher than developing a cancer therapy. To beat antibiotic resistance in bacteria we have to develop antibiotics that act against multiple targets or products of multiple genes.
“These targets have to be in the membrane or cell wall and they need to contain genes that require multistep mutations to make the bacteria resistant.
“For example, although rifampicin is 100 times more potent than vancomycin, it is a poor antibiotic because it only requires bacteria to have one point mutation to become resistant, whereas vancomycin requires many.”
Another reason why fewer antibiotics are coming to market might be due to the lack of approvals of near-market antibiotics. According to Dr. Alder, the FDA is more cautious about this drug class after Ketek™. The Sanofi-Aventis (www.sanofi-aventis.com) antibiotic to treat sinusitis and lung infections caused a rare but serious side effect, resulting in three deaths in 2006 from liver damage.
Against such a backdrop, it’s easy to see why developing novel antibacterial therapies is the road-less-travelled by big pharma and biotechs firms. A few brave souls, however, have ventured in and are showing some promising results.
Both New Haven-based Rib-X Pharmaceuticals (www.rib-x.com) and Prolysis (www.prolysis.com) in Oxford, U.K., presented novel approaches to designing new antibiotics.
“The bacterial ribosome is a highly validated target for antibiotics,” said Albert Collinson, Ph.D., CBO of Rib-X, “and we at Rib-X used an approach of structure-driven drug design to build a substantial database of 3-D information that enables an understanding of exactly how old and new classes of antibiotics bind to and inhibit the ribosome.
“Using this information in conjunction with the company’s computational chemistry software, we are able to more rapidly and efficiently design antibiotics that target the ribosome. Our discovery process reduces the cost and time necessary for us to identify new antibiotics that target the most resistant bacteria and address unmet medical need.”
Rib-X has produced RX-1741, an oxazolidinone antibiotic that exhibits activity against methicillin-resistant Staphylococcus aureus (MRSA) and other gram-positive organisms as well as Haemophilus influenzae and the atypical pathogens such as Legionella that can cause respiratory tract infections.
Dr. Collinson presented data from a Phase II study in which RX-1741 was compared against market leading Zyvox® (linezolid) to treat uncomplicated skin infections. The interim analysis showed that of the 39 patients treated with RX-1741 orally, either once a day or twice a day, all were cured and none experienced secondary lesion formation.
“In our Phase II study,” added Dr. Collinson “the predominant pathogen isolated was MRSA, against which RX-1741 is fourfold more potent than linezolid.”
Furthermore, according to Dr. Collinson, RX-1741 has been well tolerated in this study with only minor gastrointestinal complaints reported. Rib-X plans to continue to develop this compound and will look to identify a strategic partner to assist in the development and commercialization of RX-1741.
Prolysis has also used a structure-based approach by making crystals of the FtsZ protein, which is located in a ring at the edge of the bacterial septum. Inhibiting FtsZ’s activity prevents cell division.
Using molecular docking, Prolysis identified a series of inhibitory compounds, one of which, CDI-936, has shown promising activity against S. aureus.
“With S. aureus, CDI-936 binds to FtsZ inhibiting septum production during cell division, the cell balloons, and because it cannot divide, it dies,” explained Lloyd Czaplewski, Ph.D., research director for Prolysis. “One point mutation in FtsZ can confer resistance to the compound series, but the frequency is low, and we are working to reduce this. Therefore, we believe CDI-936 is still a good candidate for further development.”