A new age for drug discovery

In the last fifty years, phar­ma­ceu­tical com­pa­nies have spent tens of bil­lions of dol­lars trying to find new classes of antibi­otic drugs. Only one has made it into clin­ical prac­tice. Seem sur­prising to you? Yeah, me too.

At the same time, antibac­te­rial resis­tance has been rising, meaning the pathogens that infect us are get­ting better and better at staying alive. If we con­tinue like this, said biology pro­fessor Kim Lewis, “we’ll go back to the age of epi­demics and pandemics…society is at risk.”

The stan­dard approach for facil­i­tating drug dis­covery has been to pump more money into the system. “But this is not about a lack of money,” Lewis said. “It’s the paucity of ideas, not money, that did in this field.”

In today’s issue of Nature mag­a­zine Lewis’ essay “Recover the lost art of drug dis­covery” lays out a clear roadmap for what went wrong in the field, what worked and where we should go from here.

During the “golden age” of antibi­otic dis­covery in the 1940s, the pri­mary approach, invented by Selman Waksman, was to screen soil microbes for their ability to pro­duce nat­ural antibi­otics. Large phar­ma­ceu­tical com­pa­nies got rich with this method, Lewis said. But over time the approach col­lapsed: the same com­pounds emerged over and over again. As it turned out, only tiny frac­tion of all bac­teria could be cul­ti­vated in the lab.

In a 2002 article in Sci­ence, Lewis and pro­fessor Slava Epstein pre­sented a novel strategy for cul­ti­vating pre­vi­ously uncul­ti­vated bac­teria. “The idea was to grow bac­teria in their nat­ural envi­ron­ment,” Lewis explained. This strategy opened the door for revi­tal­izing the Waksman plat­form, which had pre­vi­ously been use­less for 99 per­cent of bac­teria, the so-​​called “uncul­tivable” bac­teria. Their teams at NU are now col­lab­o­rating with Novo­Bi­otic, a Biotech startup in Cam­bridge, MA, that licensed this inven­tion, to dis­cover novel antibi­otics from pre­vi­ously uncul­tured bacteria.

The 1940s and 50s also saw the heyday for syn­thetic antibi­otic dis­covery. “When the Waksman plat­form col­lapsed, the industry came up with two new log­ical approaches,” Lewis said. First was rational design, in which syn­thetic chemists cre­ated new com­pounds that specif­i­cally tar­geted the pro­teins inside pathogens based on their mol­e­c­ular struc­tures. These failed, how­ever, because they were inca­pable of pen­e­trating the com­plex bac­te­rial cell envelope.

The second approach was high-​​throughput screening, which tests thou­sands of syn­thetic com­pounds in par­allel for their tar­geting abil­i­ties. Again, the dif­fi­culty of pen­e­tra­tion pre­vented this oth­er­wise extremely suc­cessful method from gaining trac­tion in the antibi­otic dis­covery field, said Lewis.

In his essay, Lewis pro­poses to estab­lish a set of “rules for pen­e­tra­tion.” He sug­gests char­ac­ter­izing 100 or so com­pounds that are capable of pen­e­trating the bac­te­rial enve­lope (regard­less of antibi­otic activity) and teasing out the common prop­er­ties that seem to be impor­tant for pen­e­tra­tion. “We can then build a library of com­pounds which takes these new rules into account,” he said. “Then, if you are ratio­nally designing an inhibitor you can also put into it prop­er­ties that you know are essen­tial for penetration.”

In the first sen­tence of the essay, Lewis says “the more we know about antibi­otics, the fewer we can dis­cover.” The problem, he explained, is that every time the industry has tried to improve, it has done so based on imper­fect knowl­edge. Lewis believes we have finally come full circle, and are now in a posi­tion to revi­talize the lost art of drug dis­covery. He is working on a second article geared toward fellow micro­bi­ol­o­gists that will out­line the sci­en­tific require­ments to make his vision a reality.