Do we need more broad-spectrum antibiotics? NAD-dependent DNA ligases as drug targets.

These enzymes are excellent targets for antibiotic development. But successful development may end up degrading public health.

DNA ligases perform an essential function in all organisms, that of joining broken DNA strands together.

From DNA ligation

They can use either ATP or NAD+ as energy sources to drive the joining reaction.

NAD ligases are never found in eucarya (including humans) and are found in all bacteria

Black checks indicate that the enzyme is found in all members of the class
From DNA ligases: progress and prospects.

From a drug development standpoint, all the ducks are in a row: there are high-resolution crystal structures of NAD+-ligases available, and the enzymes readily lend themselves to high-throughput screening assays. All of the very sophisticated and powerful tools of modern medicinal chemistry can be brought to bear to identify drug candidates.

The intracellular location of these enzymes presents a challenge. In order to be effective, a ligase-targeting antibiotic has to pass through the bacterial cell wall and cell membrane. That’s always harder with Gram-negative bacteria (e.g., E. coli, Klebsiella, Pseudomonas), because they have an additional cell membrane layer that blocks many antibiotics:

From Cell Wall Structure

The most promising ligase-targeting antibiotic candidates described so far are all less effective against Gram-negative bacteria[1] . These bugs make up the majority of problematic pathogens[2] . A ligase-targeting antibiotic that works only against Gram-positives would not be a tremendous advance.

But let’s say that these technical problems (and the economic issues of antibiotic development) are resolved. We’d have a new antibiotic that treats many kinds of infections, saving many lives. That would be great news, right?

I’m not so sure.

Our response to antibiotic resistance has been much like our response to road congestion in sprawling cities: we just build another one. The problem is temporarily alleviated; development/clinical practice is built up around the new solution; congestion/resistance inevitably re-emerges; the cycle repeats. A new broad-spectrum antibiotic would no more improve public health than a new six-lane highway improves civic health.

Broad-spectrum antibiotics enable worst-practices in antimicrobial therapy. There is no need to identify the infecting organism, and thus no need to determine if an infection is viral or bacterial. Doctors submit to patient demand to get the antibiotic as a preventive measure or just-in-case. Surgeons have less fear of complications from surgical-site infections, and hospitals relax their infection control efforts.

And then when resistance emerges – as it always does[3] – we are even more entrenched in an unsustainable set of practices that are doomed to failure.

We need new antibiotics. But the antibiotics we need are those that can be precisely targeted to specific organisms[4] . By their nature, narrow-spectrum antibiotics require a precise diagnosis and must be used more sparingly. Because they kill only target organisms, there is no selective pressure on non-target organisms, which serve as reservoirs of resistance factors.

Perhaps most importantly, they are far less likely to disrupt our gut and skin microbiota. An increasing body of evidence links antibiotic use, especially broad-spectrum antibiotics, with a range of metabolic and inflammatory disorders[5] . These disorders are a far greater burden on public health in developed countries than are bacterial infectious diseases. New broad-spectrum antibiotics, used imprudently, could well result in a negative impact on health.

That’s not the result that antibiotic developers are hoping for, but it might be the one we get.

Footnotes

[1] https://www.ncbi.nlm.nih.gov/pmc…

[2] Bad Bugs, No Drugs: No ESKAPE! An Update from the Infectious Diseases Society of America | Clinical Infectious Diseases | Oxford Academic

[3] Q&A: Antibiotic resistance: where does it come from and what can we do about it?

[4] Novel Approaches Are Needed to Develop Tomorrow’s Antibacterial Therapies

[5] https://www.ncbi.nlm.nih.gov/pmc…