Finding Entirely New Drugs
Dr. Payne said that GlaxoSmithKline recognized that antibiotic development required the “great science going on outside of GSK” as well as its internal programs. “We wanted to work with other companies and spread our scientific footprint in what we did in antibacterials to explore things that hadn’t been explored before.
“We had an opportunity in 2009 to rewrite our strategy and formed autonomous small discovery units including one focused on antibacterials,” Dr. Payne said. The benefit of that strategy, he told GEN, was a flexible, imaginative approach based on unexpected mechanisms that were not necessarily predictable with conventional drug development approaches.
As a result of actively collaborating with other companies and forming an in-house basic research department, GSK has two novel antibiotic candidates: GSK2251052, a protein synthesis inhibitor, and an inhibitor of bacterial peptide deformylase.
GSK2251052 originated from a discovery alliance with Anacor Pharmaceuticals and has completed Phase I trials. It is a boron-containing small molecule that blocks protein synthesis by inhibiting aminoacyl-tRNA synthesis in Gram-negative bacteria. The agent binds to the editing domain of a specific tRNA molecule, interfering with addition of the amino acid leucine and disrupting the appropriate sequence of amino acids, which eventually foils protein synthesis.
“No other known antibiotics work via inhibiting leucyl tRNA synthetase,” Dr. Payne pointed out. The marketed topical antibiotic Mupirocin targets isoleucyl tRNA synthase. “Bacteria in the clinic are totally naive to this mechanism and don’t have a resistance mechanism around it.”
Another approach, gained by GSK through a 2008 alliance with Mpex Pharmaceuticals, explores inhibitors of bacterial efflux pumps. These pumps, intrinsic defense mechanisms in Gram-negative bacteria, expel toxins including antibiotics before they can reach their targets and kill the bacteria.
Higher intracellular antibiotic concentrations achieved through efflux pump inhibition could potentially increase the potency and pharmacological barrier against other drug resistance mechanisms. This may help maintain or even enhance the potency of otherwise effective antibiotics.
Dr. Payne echoed a view shared by drug developers that “we have to make sure that what we have done is sustainable, through developing a flow of diverse antibacterials. Just one new antibacterial today won’t solve the problem. What’s happened recently is that companies have withdrawn from the area so there’s a big gap in the pipeline, and we need to ensure it won’t happen again.”
Some novel compounds are emerging from newer players. Polymedix Biopharmaceuticals is developing antibacterials based on naturally occurring defensins, peptide molecules that have evolved in eukaryotes to protect them against bacterial infections.
PolyMedix founder, president, and CEO Nicholas Landekic explained to GEN that although peptides mimicking defensins have potential as antibiotics, their size, stability, tissue distribution, and toxicity limit their use as systemic drugs, making them most useful as topical agents.
PolyMedix got around this, he says, by designing and developing small synthetic organic compounds that mimic the defensins’ key molecular feature, the amphiphilic helix found in the natural molecules. The compound design exploits the inherent differences in charge and lipid composition between bacterial and eukaryotic cell membranes and affect only bacterial membranes. “The only thing that’s relevant for activity is a very specific arrangement of charged and hydrophobic groups,” Landekic pointed out.
Unlike conventional antibiotics with biochemical targets, Landekic added, these molecules act to kill bacteria by physically disrupting bacterial cell membranes. “Just like the natural host defense proteins, as soon as they come in contact with the bacterial membrane, our drugs form a pore in the membrane. Water then enters the membrane, causing it to swell, which disrupts the membrane’s inner structure. This destabilization results in membrane destruction.”
Landekic reported that the company has completed three Phase I studies in a total of 123 subjects with its lead compound, PMX-30063. Last September, a Phase II study in ABSSI for all drug-sensitive and drug-resistant hospital-based Staph infections began. “We expect to have final results by the end of the year for the full 200 patients, with an interim analysis planned after the first 80 patients have completed.”
While acknowledging the financial, regulatory, and research hurdles that have contributed to the dearth of new antibiotics, the Infectious Disease Society of America (IDSA) said this April that “the time has come for a global commitment to develop new antibacterial drugs.” In its paper entitled “Bad Bugs, No Drugs,” IDSA proposed its 10 x ’20 initiative, citing measures required to create 10 novel antibiotics by 2020.
The society called for global stakeholders to capitalize on each other’s strengths to create a long-term, sustainable R&D infrastructure model that provides incentives for both antibacterial drugs and related diagnostic research enterprises.
Large companies like GSK, with a historical commitment to and deep knowledge of antibiotic development, that stay in the game can help realize the goal of the 10 x ’20 initiative. So can smaller, highly innovative and strategically nimble companies with unique discovery platforms with sufficient support mechanisms in place to do it on their own.