In emergency situations, broad-spectrum antibiotics have their place. But their indiscriminate use has led to a resistance crisis that already kills tens of thousands of people annually in the U.S. alone.

If left unchecked, antibiotic resistance has the potential to undo decades of progress, not just in the treatment of infectious diseases but also in other medical fields such as surgery that are dependent on the ability to prevent infectious complications.

And yet, market mechanisms are as much of a problem as scientific challenges in preventing what could be 10 million deaths annually by 2050.

“According to the pharma people, they are not going to get a return,” James Knighton told BioWorld.

And for smaller startups, for whom antibiotics can make more business sense, it is hard to get the necessary funding to develop them because “every VC has their eye on one thing, and that’s your exit.”

Knighton is the CEO of Pylum Biosciences Inc. And over the last 15 years he has “busted more than one blade on this rock called antibiotics” at both Pylum and its precursor company, Avidbiotics Corp.

Knighton said that for commercially successful development of antibiotics, “we’ve got to stop and rethink, completely, the way we do antibacterial activity.”

In particular, he said, “you’ve got to change the cost structure.”

That is not to argue that antibiotics are properly valued either by society as a whole, or by hospitals.

“Almost inarguably, the most important drugs ever invented by man are antibiotics,” Knighton said. “And we take them for granted; we think we should get them for three bucks.”

Even for patients with extremely serious infections, the way hospitals do their accounting means that there can be a reluctance to pay a premium for a newer, more effective antibiotic, even if that antibiotic might be able to prevent a weeklong stay in the intensive care unit to the tune of tens of thousands of dollars.

But the pharma business model fails to work for antibiotics not just because they are undervalued.

It also fails because resistance to antibiotics is inevitable, and the best way to delay the inevitable is to not use new drugs in any but the most dire circumstances.

To have an ongoing supply of effective antibiotics in the face of such inevitable resistance, Knighton argued, will take addressing “the cost end, not the pricing end.”

Pylum’s solution to that conundrum is a class of antibiotics the company has called avidocins.

Joseph Mougous, University of Washington and Howard Hughes Medical Institute

Like the T6SS system that is the basis of the cells developed by Joseph Mougous, professor of microbiology and biochemistry at the University of Washington and an investigator of the Howard Hughes Medical Institute, and his team, avidocins are based on proteins used by bacteria against competing bacteria.

Pylum has developed avidocins targeted to five different pathogenic bacteria, as well as two microbiome components. Furthest along, though still preclinical, is Av-CD291.2, which targets Clostridium difficile.

A separate program targets bacteria important for food safety and animal health.

For the most part, the avidocins are indistinguishable.

They are “99.9% similar, except for [their] binding tip,” Knighton said. There are “only a few molecules at the very tip that you’ve got to change” to retarget the protein.

General method for specific gram-negatives

Another potential possibility, reported by researchers from the University of Washington, is the engineering of bacteria with retargeted T6SS, or Type VI Secretion Systems, as programmed inhibitory cells (PICs).

Gram-negative bacteria use T6SS against each other as they jockey for position in the microbiome. Bacteria produce multiple toxins, and when they come into direct contact with each other in the microbiome, they will inject those toxins into each other.

On its own, T6SS is as broad-spectrum as any antibiotic. “It doesn’t have a receptor, so it will target organisms very broadly,” Mougous told BioWorld.

However, “it needs to make contact with a cell for a prolonged period in order for toxin delivery to occur.” T6SS-based bacterial killing will only occur if two bacteria are within at least 200 nanometers of each other for several minutes – “and that’s where our cell-cell adhesion strategy comes in.”

Mougous and his colleagues used nanobodies, which are the single-domain antibodies derived from camels, to allow toxin-secreting cells to dock to specific target cells. In work published online in Cell Host & Microbe on May 28, 2020, they showed that they were able to target PICs to cells expressing BamA, a widely expressed bacterial surface molecule, and intimin, which is expressed by some pathogenic strains of Escherichia coli. In both cases, the engineered PICs were able to specifically kill their target populations in cell cultures of mouse-derived fecal microbiomes without affecting other cell types.

Mougous noted that PICs and avidocins are “very different in terms of their biology… one is a living organism and the other is a particle.”

Nevertheless, both approaches are similar in that they could, in principle, be an antibiotic platform technology of sorts, rapidly targetable to new pathogens.

Nanobodies, Mougous said, can bind to any cell that has an antigen on the surface – “that’s a very low bar.”

The T6SS system is limited to gram-negative bacteria – it would not, for example, be useful against the gram-positive C. difficile. But there are analogous systems that could be used for gram-positives.

And “because of their ability to be displayed on the cell surface and how easy they are to work with… you can start with tremendous libraries of nanobodies,” Mougous said.

If a new nanobody is inserted into an inhibitor strain, “now it’s been completely repurposed to recognize a new bacterium,” he said. And like the repurposing of avidocins, “that could potentially happen in a number of weeks.”

So far, there is skepticism about the idea of rapid retargeting. Pylum’s Knighton described it as a belief that “it doesn’t change the dynamics – it’s still going to cost a billion dollars, and when you want to change the binding site to go against a new bug, it’s going to cost you a brand-new billion dollars.”

Certainly, for the dynamics to change, regulatory agencies will have to become “far more understanding about how to get drugs through the development cycle in a more efficient cost-effective way,” Knighton said. “That’s going to be one of the big elements here – like new technologies in general.”

But such change is possible, he said, and there is already a working example of how such antibiotics could be handled by regulatory authorities: “We get a flu vaccine completely redone for every fall season.”

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