Threat of Antiobiotic Resistance
Jutta Heim, Ph.D., CSO of Basilea Pharmaceutica (www.basilea.com), a Roche drug discovery spin-off, described how they are responding to the growing threat of antibiotic-resistant bacteria. Basilea is focused on antibacterials, antifungals, and anticancer drugs, with three products currently in Phase III—ceftobiprole, alitretinoin (for dermatitis), and isavuconazole, an anti-fungal. Ceftobiprole is being developed as an anti-MRSA (methicillin-resistant Staphylococcus aureus) broad-spectrum antibacterial with Johnson and Johnson.
“Emerging antibiotic-resistant infections are one of the most serious problems our hospitals face today,” Dr. Heim said. “Many people are dying from this cause, regardless of their underlying illness.” The antibacterial market was worth $29 billion in 2005, of which $8 billion was spent in hospitals. There are already many powerful antibacterials, but, even while resistance has increased the need for new drugs, several big pharmas pulled out of this area. Between 2002 and 2006, only a few new antibacterial drugs came onto the market.
Only four drug targets appear to be useful for antibacterials: cell wall biosynthesis, transcription, translation, and metabolism. Bacteria can develop resistance against all antibacterials, regardless of their target or class, explained Dr Heim. They then disseminate this resistance through horizontal gene transfer. MRSA has also become coresistant to other antibacterials.
The mechanism of resistance to marketed beta lactam antibacterials, which target the cell wall, is attributed to the presence of an extra penicillin binding protein (PBP2´) in the resistant strain, to which beta lactams bind only weakly, allowing it to continue producing cell wall.
Dr. Heim described how Basilea has attempted to overcome this with the development of ceftobiprole, which is a re-engineered cephalosporin. Clinical trial data published earlier this year show comparable efficacy with combination vancomycin/ceftazidime control in complicated skin infections, including diabetic foot ulcer and MRSA infections.
“The most important result for us was that in serial passage experiments, where resistance might be expected to develop, ceftobiprole showed a low propensity for the development of resistance, compared to fluoroquinolones and linezolide,” said Dr. Heim. A detailed analysis of the interaction between the PBPs and the new antibacterial shows how it converts PBP2´ from being resistant to being sensitive again.
Meanwhile, the Infectious Disease Society of America has warned against a second wave of antibiotic resistance, coming from the Gram negatives, with Klebsiella, Pseudomonas, and Acetinobacter being the new danger bugs putting patients’ lives at risk. These species have a variety of different mechanisms with which to fight antibiotics, Dr. Heim warned. Basilea’s approach to the Gram negative threat is to develop new antibiotic combinations, similar to amoxicillin/clavulanic acid and piperacillin/tazabactam, which have been successful in the past. This approach requires industrial scale profiling and generation of millions of datapoints to hit upon the optimal combination of many potential antibacterials.
In early work, the Basilea team says it obtained promising results with one combination against a pan-resistant strain of K.pneumoniae from Greece.