Getting the Upper Hand on Superbugs

Humans

Since the first use of antibiotics more than 75 years ago, humanity has been locked in an ongoing arms race with bacteria. Right now, it seems the bacteria are winning.

In the past, every advance in treatment opened a window of virtually unchecked efficacy. Resistant bacterial strains inevitably evolved—but when they did they were met with new, improved antibiotics. Today, however, the evolution of resistance, fueled by the overuse and misuse of antibiotics in medicine and agriculture, has outpaced the development of new medicines. 

This is particularly worrying in the hospital setting, where multidrug-resistant superbugs threaten an incredibly vulnerable patient population. If we fail to reverse this trend by continuously developing new classes of antibiotics, we risk returning to a time when even minor infections, injuries or medical procedures routinely turn deadly. Developing these fundamentally new medications is much easier said than done, but some recent discoveries may help us fight resistant bacteria in new and surprising ways. 

THE GREAT (AND TERRIBLE) ‘ESKAPE’

Our research group at Genentech is particularly interested in the so-called ESKAPE pathogens, a gang of notoriously dangerous bugs (the name is an acronym for Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter species). These bacteria, the leading causes of hospital-acquired infections, are rapidly developing resistance to more than one drug.

There are two types of ESKAPE pathogens: gram-positive and gram-negative. Both are potentially deadly and can be challenging to treat, but for different reasons.

For gram-positive bacteria, we actually have antibiotics that work quite well. Yet strains like methicillin-resistant Staphylococcus aureus (MRSA) still kill thousands of people every year. One reason is a clever behavior on the part of the bacteria. They’re capable of hiding inside immune cells where antibiotics can’t find them, and using these cells as microscopic Trojan horses to spread through the body. To overcome this problem we designed a delivery system, called an antibody-antibiotic conjugate, which can find where they are are hiding and attack them from the inside. This novel approach is now being tested in the clinic.   

With gram-negative bacteria, however, it’s not enough just to get the medicine to the bugs. The problem here is that we don’t have effective antibiotics. Gram-negative bacteria have unique features that make them especially prone to drug resistance. First, they have an extra layer of protection, called the outer membrane. This nearly impenetrable cell wall prevents many powerful antibiotics from ever reaching their targets. To make matters worse, many gram-negative strains have already developed resistance to the handful of antibiotics that are able to penetrate the outer membrane.

To have even a shot against these superbugs, we need an entirely new class of antibiotic. The hurdles are so challenging that scientists haven’t been able to do this for more than 50 years. Until now.

IRRESISTIBLE CHEMISTRY

In a study just published in Nature, our group describes a new class of antibiotic we developed that may provide fresh hope against the deadliest superbugs. 

Our discovery efforts started with arylomycins, a class of molecules that target a protein called signal peptidase, which lies just beneath the outer membrane in gram-negative bacteria. Because signal peptidase is essential for bacterial survival, it’s an obvious antibiotic target. However, the activity of arylomycins is currently limited to a small subset of gram-positive bacteria, which have no outer membrane. Their efficacy against gram-negative bacteria is modest at best—and none have shown activity against ESKAPE pathogens.

Nevertheless, we knew signal peptidase was tantalizingly just out of reach in the space between the outer and inner membrane. If we could only get past the outer membrane, and overcome naturally occurring resistance mechanisms, we’d have a real shot at making a novel antibiotic. 

During a five-year medicinal chemistry effort, which originated in a research collaboration with RQx Pharmaceuticals, we made iterative modifications, tinkering with and modifying the chemical structure of arylomycins to try and succeed where previous attempts have failed. We generated over a thousand new molecules until we found ones that could penetrate the outer membrane and engage the signal peptidase with exquisite affinity. And perhaps most importantly, the modifications resulted in a molecule that bound and inhibited signal peptidase in a completely novel way, overcoming known arylomycin-resistance mutations.

This was a moment of true excitement for us. We had created an entirely new class of antibiotic that could kill common gram-negative pathogens. But our goal wasn’t just to kill laboratory strains of bacteria. The ultimate goal was to kill multidrug-resistant pathogens that are actually affecting patients. 

It was time to put our discovery to the test. So we contacted the Centers for Disease Control and Prevention (CDC) to get samples of their most treacherous gram-negative ESKAPE pathogens—a veritable most-wanted list of the worst bacteria on the planet. Incredibly, the new antibiotic worked against every one. This pre-clinical research showed that its efficacy held up even in bacteria that have developed resistance to nearly all other classes of antibiotics. 

TIME IS EVERYTHING

The ongoing arms race against bacteria is inherently a race against time. Hospital-borne infections have the potential to quickly spread to local and global communities. Novel classes of antibiotics are crucial because they allow us to reset the clock, providing new weapons that even the deadliest superbugs have not yet evolved to resist.

There’s more to be done, but we’re excited about the potential of our new antibiotic class. Similar approaches could be applied to other types of antibiotics, potentially opening additional, faster avenues for creating fundamentally new antibiotics in the future.

The battle against superbugs will never truly be over. But for the moment, we may have a chance to gain the upper hand. 

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