Playing with Wild Cards
The treatment of hospital-acquired bacterial infections is costly to the healthcare system. George Miller, Ph.D., research fellow of Achaogen, noted that one recent study demonstrated that patients who developed a hospital acquired infection each incurred an additional $156,704 in costs, on average.
“Multidrug resistance strains are emerging as natural, evolutionary bacterial responses that ultimately defeat any antibiotic. Today, formerly effective antibiotics such as cephalosporins, carbapenems, aminoglycosides, and fluoroquinolones have been severely compromised by resistant strains. The wild cards are the rate of resistance and the virulence of pathogens.”
Achaogen is developing first-in-class agents, as well as enhancing previously successful approaches. The company’s lead product is a “neoglycoside” or novel aminoglycoside, ACHN-490, that entered into a Phase II trial in March. “A double modification to an existing aminoglycoside produced a neoglycoside.”
“ACHN-490 shows activity against multidrug resistant gram-negative pathogens and methicillin-resistant Staphylococcus aureus in preclinical studies. It is a broad-spectrum IV infusible therapy.”
Dr. Miller said that the compound “appeared safe and well tolerated in Phase I trials. Animal studies provided encouraging data that the compound was effective in murine lung tissue. It also demonstrated a more reduced potential for ototoxicity than comparator drugs in a guinea pig model.”
Overall, Dr. Miller sees ACHN-490 as a front-line antibacterial, particularly useful in the critical-care arena. Achaogen has four additional antibacterial drug programs in preclinical development.
“We don’t discover drugs, we design drugs,” noted John Finn, CSO at Trius Therapeutics. Dr. Finn discussed the company’s two major strategies for producing antibiotic compounds: structure-based drug design (SBDD) and focused antisense screening technology (FAST).
“Using high-throughput structural biology, we rapidly generate multiple ligand-protein structures. We employ SBDD tools to enhance drug properties, spectrum, potency, and target inhibition. The FAST platform consists of a set of bacterial strains that contain antisense DNA fragments that can be regulated to inhibit production of the target protein.
“Compounds that act on the protein downregulated by the particular FAST strain require significantly lower concentration of the test compound to inhibit growth. These strategies are a powerful approach for natural product discovery.”
Dr. Finn provided an example of Trius’ methionyl-tRNA synthetase (MetRS) program. “The aminoacyl tRNA synthetases are an underexploited class of antibacterial targets. These enzymes are critical for protein synthesis. Inhibitors represent a new class of antibiotic agents with good gram-positive activity. The traditional means for discovering antibacterial agents to this target yielded highly serum-bound agents. SBDD and FAST yielded potent gram-positive antibacterial agents that were effective in vivo within six months using one chemist.”
Another approach is to outsmart bacteria. “Smart bugs are essentially scanning bacterial genomes for multiple resistance mechanisms. One strategy to outsmart emerging resistance is to inhibit two critical bacterial targets with a drug. This strategy works particularly well when inhibition of the targets is synergistic. Synergy is an underrated tool.”
Trius has discovered agents that inhibit both MetRS and bacterial dihydrofolate reductase, an enzyme critical for bacterial growth and replication. “Combining activities in a single compound offers solutions to several antibiotic issues,” Dr. Finn said. “In the future, we expect to see an increased emphasis on synergistic drugs that can be used in reduced amounts, and thus, provide a higher safety profile. They can also yield a wide spectrum of activity and more easily avoid resistance.”