The Pew Trust has come out with a document that I hope makes an impression: their Roadmap for Antibiotic Discovery. Every year the the bacterial resistance problem gets a bit worse, and the most we can do is make it get worse at a slightly slower rate. As long as we want to kill bacteria, we’re going to be in an arms race with them. (I’ve actually done antibiotic drug discovery myself, and killing bacteria (without killing everything else) is very hard indeed).
You can find quite a few people who are convinced that Big Pharma, unable to make their customary billions, have callously abandoned every one to bacterial death, but as I’ve written several times before, it didn’t quite work like that. Several large companies did pull out of antibiotic research, for sure, but several didn’t. The companies that didn’t pull out, though, never made much progress, and it’s the combination of poor prospects and return on investment that has dragged the field down. If you went to a big drug company and asked if they’d like to have a new drug like linezolid or ciprofloxacin, with the prospects that each had when they first hit the market, they’d sign right up. But divide that by the chances of getting one of those, and it’s not a good idea. Put simply, if the antibiotics divisions of GSK or AstraZeneca (to pick two that kept going) had been separate independent discovery companies, they would have been the largest things in the field. And they would have gone bankrupt. Years of work in both shops led to no marketed drugs – the money flowed out constantly and nothing ever flowed back in.
The Pew roadmap sums up the situation this way:
New discoveries dropped precipitously from the 1980s onward. As a result, the development of antibiotics has declined, with new Food and Drug Administration (FDA) approvals for these drugs falling from 29 during the 1980s to nine in the first decade of the 2000s. All antibiotics approved for use in patients today are derived from a limited number of types, or classes, of antibiotics that were discovered by the mid-1980s (Figure 1). This is even more concerning than the decline of drug approvals because resistance to one antibiotic often leads to resistance to multiple antibiotics within the same class. While drugs can be categorized or classified in a variety of ways, for the purposes of this document, antibiotic classes are based on similarities in chemical structure.
Faced with poor discovery prospects and diminishing returns on investment, major drug companies have cut back or pulled out of antibiotic research altogether. This has left much of the remaining discovery work to small, “pre-revenue” companies with no products on the market and limited budgets and R&D capacity. Most industry antibiotic development programs are primarily focused on modifying existing classes of drugs discovered decades ago to circumvent bacterial resistance and better target difficult-to-treat infections. Though essential, such incremental advances are not likely to meet the looming public health challenge of antibiotic resistance in the long term.
This is true. And one of the things I like about the Pew Roadmap is that it recognizes that the biggest barriers to finding new classes of antibiotics aren’t really regulatory or financial ones: they’re scientific. The plan calls for efforts to produce new chemical matter in the property space that antibiotics tend to occupy, which is a rather weird one compared to most other drugs and not well served by current screening libraries:
It is important to clarify that this proposed effort is not focused on broad expansion of synthetic libraries or seeking out new sources of natural products. Instead, the goal is to execute focused work to carefully vet existing chemical matter and conduct targeted synthesis and modification of new chemical matter based on what is known about antibacterials from published and unpublished sources, incorporating insights and guidance as new research findings emerge.
It will take time to determine whether conditional guidelines can be developed for Gram-negative drug entry and efflux avoidance. Meanwhile, practical and transparent knowledge-sharing mechanisms should be established to better inform discovery scientists on how to identify new chemical matter based on drug-like qualities and what is already known about the chemical properties of antibiotics. This would require collaborative research to facilitate new and directed approaches to generate and modify chemical matter. For example, working together across multiple disciplines, scientists may begin to develop new semi-synthetic antibiotic templates derived from fragment-based or natural products-based starting points that better target Gram-negative or Gram- positive bacteria.
There’s also a proposal to revisit failed natural product projects that showed some antibacterial promise, in an effort to see if the reasons for these failures can be overcome with semisynthetic derivatives and so on. The roadmap also calls for a concerted effort to work on targeting Gram-negative organisms in particular, and to do that we have to have a better understanding of their membranes, transporters, and efflux pumps. These are the barriers that make those organisms so difficult, and it’s clear that we don’t have a good enough handle on them. (For example, there are two layers of membranes around these creatures, each with different properties, so it’s hard to come up with a compound that will get across both of them at once. And each of them are lined with membrane-spanning proteins that pump a huge variety of structures – pretty much anything that’s not on the guest list – back out of the cells).
The team calls for a joint academic/industrial effort to (1) first identify what we actually know about targeting these organisms, with opening of the books on past failures, (2) come up with standardized assays to measure drug penetration and measure existing compound collections against them, while (3) at the same time working on efflux pump and membrane disruption ideas. To that first point:
There is growing concern that as industry teams are downsized or shuttered, antibiotic scientists have moved to other firms, shifted to different biomedical areas, or retired, leading to the loss of valuable institutional knowledge and expertise. Antibiotic discovery has a long history, but much of the published research is buried in old journal issues or out-of-print books, and other research never makes it to publication. Organizing this body of research and making it accessible to the scientists who need it is critical for advancing discovery. Valuable knowledge may include compilations of screens that have been run before and information on past research programs. While much of this information is publicly available, what may be most useful is an account of what projects failed, and why.
Outside of these traditional antibiotic ideas, the document also has a section for working on some of the less standard ones: going after virulence factors, for example, or using immunotherapy approaches, drug delivery modes that haven’t been explored enough in antibiotics, predatory bacteria (an area that’s beginning to be explored with DARPA funding), etc. There are a lot of areas that have seen work on and off (the polymyxin membrane-disrupting compounds, iron-uptake pathways as a route to drug entry), that need a more concerted effort. For many of these, we’re going to have to figure out what appropriate development pathways will even look like.
Another area that gets attention is something that you’d think would have been explored more in antibacterials, but hasn’t: combination therapies. This is the rule in antivirals – you hit several mechanisms at once to lower the chance of resistance, but you really don’t see mixed-mode therapies in antibiotic work as much. The roadmap calls for an exploration of this area, with special attention to trying to revive the single-target agents that have failed over the years for lack of efficacy on their own.
There are many more details in the plan itself, so if you’re into this sort of thing I encourage you to read it. The whole thing seems very sensible and well-aimed, but the tough part now will be implementing it, because it won’t be easy and it won’t be cheap. One encouraging thing, though, as a correspondent put it, is that when it comes to Congress, “there’s no constituency for multidrug resistant organisms”. If some prominent politician wants to make a Joe Biden-like splash in addressing a major public health problem, this looks like an excellent place to do it.