Science1 publisher2 min readPublished
Corramycin kills drug-resistant TB cultures by locking gyrase onto severed DNA
A team at HIPS, the Institut Pasteur and Universite Paris Cite reports that corramycin attacks the same enzyme as fluoroquinolones by a different route and stays active against isolates those drugs no longer touch. An earlier program dropped the compound over production cost.
The Scientist · Science desk
What happened
- A screen of an extensive library of myxobacterial extracts against Mycobacterium tuberculosis picked out corramycin as the candidate worth following up.
- In laboratory tests the compound was effective against various forms of the pathogen, including strains taken from patients that already resist commonly used antibiotics.
- Corramycin binds DNA gyrase after the enzyme has cut the DNA and blocks it from rejoining the strands, so the bacterium's own enzyme leaves the genome damaged enough to kill the cell.
- Sanofi and Evotec had already run a corramycin program aimed at Gram-negative urinary tract infections and stopped it because the compound cost too much to produce.
Compiled by The ScientistSomething wrong?How this is made
Why it matters
- capability A solved structure of the compound on gyrase means chemists can try to fix corramycin's drug-like weaknesses while keeping the binding that fluoroquinolone resistance does not block.
- cost Production cost is what stopped the last program on this molecule, and it is still the blocker; a better structural picture of the target does not lower it.
- decision Any revived corramycin effort starts with process chemistry and pharmacokinetics work, before a clinical question can be put to it at all.
- constraint Nobody with drug-resistant tuberculosis is closer to a treatment this month. The evidence stops at enzymes, structures and cultures, and corramycin remains a lead compound.
DNA gyrase is an enzyme bacteria need to copy their genetic material, and the fluoroquinolones already in clinical use act on it [19][10]. Franziska Fries, a researcher in the Microbial Natural Products department at HIPS, said corramycin "attacks its cellular target, DNA gyrase, in a different way than fluoroquinolones" [9]. She said this "also explains why corramycin remains effective against fluoroquinolone-resistant bacteria" [8]. Cryo-electron microscopy gave the team a direct view of where the compound sits on the enzyme [12].
The published account does not give minimum inhibitory concentrations, the mutations carried by the resistant clinical isolates, or any result in an infected animal [18].
The new target gives HIPS a reason to go back to a compound it had set aside [14]. Rolf Muller, the institute's scientific director, said corramycin is "a promising starting point for the development of new active compounds against drug-resistant tuberculosis" [15]. He also said that "before it can be developed into a drug, the production of the substance, its activity in the human body, and its pharmacokinetic properties, in particular, must be further optimized" [16].
The WHO counts more than 10 million new tuberculosis cases a year [1]. That is at least 27,000 people a day [17]. Treatment runs for months and combines several antibiotics, and against resistant strains the available drugs work only partly [2][3]. The work appeared in Advanced Science, from a collaboration led by HIPS, the Institut Pasteur and Universite Paris Cite [4], with Stephanie Petrella in Paris and, through the German Center for Infection Research, groups led by Jan Rybniker at the University Hospital of Cologne and Norbert Reiling at the Research Center Borstel [7].
What to watch
- Whether anyone funds the process chemistry needed to make corramycin at a cost a tuberculosis drug can carry.
- A mouse or other animal infection study showing whether the activity seen in culture also appears in an infected animal.
- Frequency-of-resistance work: how quickly M. tuberculosis raises gyrase mutants that resist corramycin itself.