When Dr. Ankit Mahadevia founded Spero Therapeutics in 2013 to discover new antibiotics, he thought he would encounter some doubters. Though the spread of antibiotic-resistant bacteria was alarming the world's health agencies, the drug industry had turned away from the field for a reason: The drugs were hard to make and hard to profit from.
But, Mahadevia said, people have responded positively to the company and its science in the years since — an indication that the work done by a small number of biotechnology and pharmaceutical companies is fueling at least some optimism for new antibiotics.
"The ecosystem is starting to remake itself," he said.
Cambridge-based Spero is developing new treatments for so-called gram-negative bacteria, a class that includes E. coli. Gram-negative infections can be tougher to treat than other types because the cells have an outer membrane that acts as a barrier to drugs. One of the company's programs, which it plans to start testing in humans next year, uses molecules called potentiators to bind to that membrane and open it, allowing drugs to penetrate and attack the bacterium.
The company, which has about 20 employees, has been working out of Atlas Venture's Kendall Square offices but is moving to its own space in Central Square early next year. It has partnered with Roche Holding AG on one of its programs and has attracted investment from Merck & Co. — the two large pharmaceutical companies that, observers say, have been the most active in antibiotics recently.
Industry interest has grown because the public health alarm has been accompanied by some policy changes, including a 2012 measure called the GAIN Act, which granted longer patent protection for antibiotics and made the drugs eligible for a streamlined approval process. Federal grants and contracts prompted some companies to launch anti-infective programs over the years, and now private investors have loosened their purse strings.
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"It's certainly easier to raise money in this area today than it was three or four years ago," said Guy Macdonald, who has been chief executive of Watertown-based Tetraphase Pharmaceuticals Inc. since 2008.
But whatever excitement exists in the industry stands in stark contrast to the mood among public health officials. Just this month, the World Health Organization said resistance could reverse life-expectancy advances, and scientists reported finding a strain of bacteria in China that's resistant to the antibiotic of last resort.
Groups such as the Infectious Diseases Society of America point to the GAIN Act as a first step and are backing additional measures that would allow clinical trials of antibiotics to have fewer patients and create tax incentives for new treatments.
"Antibiotic development is nowhere close to meeting the needs that patients currently have, as well as meeting the needs on the horizon," said Amanda Jezek, vice president of public policy and government relations at the Infectious Diseases Society of America.
About 30 companies are working on antibiotics for US clinical development, only a small number of which are large pharmaceutical companies, according to the Pew Charitable Trusts, which tracks the pipeline.
And most of the drugs are modified versions of existing antibiotics — not new classes of drugs that are more effective against stronger bacteria.
"It's still not a robust pipeline, and there are still not enough companies that are currently developing these types of products," said Carolyn Shore, an officer on the antibiotics resistance project at Pew.
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Another challenge: Some companies are focused on making antibiotics delivered just in hospitals, which can be generally priced higher. But Prabha Fernandes, the CEO of Cempra Inc. in Chapel Hill, N.C., said that "there is a huge hole, a huge vacuum" for drugs for at-home use. Cempra is wrapping up phase 3 trials for its drug solithromycin, which it hopes to offer in intravenous and oral versions.
Meanwhile, companies working on antibiotics have had their ups and downs.
Tetraphase reported in September, for example, that its flagship drug eravacycline failed to meet targets in a phase 3 study in urinary tract infections. The problem, Macdonald said in an interview, was that an oral version of the drug was not as effective as intravenous methods used in other studies. The company is talking with regulators to see if it can use the data it has to apply for approval or if another study is needed.
Last year, in a $9.5 billion deal, Merck acquired Cubist Pharmaceuticals, a leading antibiotics company, in what was seen as a major investment in antibiotics and a validation of Cubist's drugs. But soon after, the company laid off employees, causing concern about slowed progress against infectious diseases.
Zeneca PLC also cut its antibiotics development staff this year and then spun out its antibiotics pipeline into a new company in Waltham called Entasis Therapeutics Inc., which has a drug for multidrug-resistant gonorrhea in Phase 2 trials, among other programs.
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Entasis has had to rebuild the infrastructure it lost in its split from Zeneca, relying more on contractors, said John Mueller, vice president of program management and early development. But it remains dedicated to antibiotic drugs, he said.
"There is a lot of work left to do," he said. "And this is going to take a consortium of efforts."
Public health officials want new drugs, of course, but they emphasize that other steps can be taken right now to minimize antibiotic resistance. In an event last week sponsored by Pew, Dr. Tom Frieden, director of the Centers for Disease Control and Prevention, warned that future drugs would also be "outsmarted" by bacteria if practices surrounding antibiotic use aren't improved.
"If we don't preserve and improve the way we use antibiotics today," he said, "then the next antibiotics that come online will also be compromised."
Andrew Joseph can be reached at andrew.joseph @statnews.com. Follow him on Twitter @DrewQJoseph. Follow Stat on Twitter @statnews.