New Antibiotics: Resistance is Futile...

Strides in Medicine have made major leaps in almost every category in cancer, auto-immune, etc.  However, on category hasn’t seen an appreciable jump since the 1960s, the world of antibiotics.
  
Widespread introduction of antibiotics started in the 40s with penicillin and streptomycin, ridding most of the prevalent diseases of the day.  Over time though, resistance development limited the lifespan of these defenses.  This gave rise a need to introduce new microorganism compounds to bacteria cells to make new antibiotics.  However, this proved limiting, for the bacteria cells penetration barriers weren’t cooperating in the lab, and would fend off anything short of soil microorganisms that could be sustained in a lab environment.  

Needless to say, the number of soil microorganisms that were resilient enough to survive in a lab environment, better known as “cultured” microorganisms, was limited at best.  In addition, this limited resource was over mined in the 60s which abruptly halted antibiotic discovery since then.  Of course, Synthetic approaches were tried, but were unable to replace the success of the soil microorganisms.

So how small was the list of microorganisms that could survive in a lab environment? In short, approximately 99% of all microorganism species in external environments were “uncultured”; hence, the problem.  

This situation may have seen a turning point.  By looking at the issue of replicating the natural environment in a lab, scientists have discovered a new way of isolating and growing uncultured bacteria. As a result, this new method has seen the rise of interesting compounds that may have opened a new genre in the field of antibiotics.

Enter the iChip, a panel device that has tiny pores (channel) that only allow a single bacteria cell to inhabit which is captured from a diluted soil solution.  After the channels are filled, two semi-permeable membranes (solid agar) are placed sealing the channels then the whole board into a beaker of the original soil. The microbes are constrained to the agar, but they can still soak up nutrients, growth factors, and everything else they need from their natural environment. And thus, the formerly ungrowable now grows. “The method has the potential to be truly transformative, giving us access to a much greater diversity of environmental bacteria than previously imagined,” says Gautam Dantas from Washington University in St Louis.

Among these new microbes, the team, led by Kim Lewis from Northeastern University, found one species that kills staph bacteria efficiently. It belongs to an entirely new genus and is part of a group that’s not known for making antibiotics. They called it Eleftheria terrae. It yielded a compound—Teixobactin—that could kill important rogues like the bacteria behind anthrax and tuberculosis, and Clostridium difficile (which causes severe diarrhoea).  
If this wasn’t amazing enough, Teixobactin was found to prevent bacteria from building their outer coats. They used it to successfully treat antibiotic-resistant infections in mice. To really test this result, the team tried to deliberately evolve strains of bacteria that resist the drug. The team exposed some of these microbes to low levels of teixobactin for several weeks, to see if resistant strains would evolve. None did.

“I thought: Aw, damn it,” says Lewis. “We discovered a detergent.”

Counter-intuitively, if you see a total lack of resistance, it usually means that you’ve discovered a compound so toxic that it’s never going to work in an actual human. Hence: Lewis’s dismay. But when his team applied the drug to mammalian cells, it wasn’t toxic at all. It seemed safe, stable in blood, and capable of protecting mice from lethal doses of MRSA (drug-resistant staph). Things were looking up.

Losee Ling from NovoBiotic Pharmaceuticals and Tanja Schneider at the University of Bonn showed that teixobactin works by withholding two molecules—Lipid II, which bacteria need to make the thick walls around their cells, and Lipid III, which stops their existing walls from breaking down. When teixobactin is around, bacterial walls come crumbling down, and don’t get rebuilt.

The drug also sticks to parts of both Lipid II and Lipid III that are constant across different species of bacteria. It’s likely that these parts can’t be altered without disastrous consequences, making it harder for bacteria to avoid teixobactin’s double-punch. This might explain why it’s so hard to evolve resistance to the drug.

This won’t work on every bacterium. Many of them, like E.coli, Salmonella, and Helicobacter, have another membrane around their cell walls that can deflect teixobactin. So does E.terrae—the microbe that makes the drug in the first place. 

That’s actually a good thing. Lewis says that many of the resistance mutations that weaken antibiotics are created by borrowing from the microbes that produce those antibiotic drugs.  But since E.terrae is impervious to the antibiotic it used to produce, teixobactin, other bacteria have nothing to borrow and develop into a resistant strain. “It started looking to us like a fool-proof case of no resistance,” he says.

Meanwhile, the team is continuing their testing on animals with the hopes of getting the FDA approval.  They are striving to make the compound more soluble, so the doses can be varied.  This is one of the first discoveries for the iChip, so one can imagine what is in store for the future.  Perhaps the antibiotic days of discovery of the 60s have returned?

“There’s no doubt in my mind that we’ll do exactly that,” he says.

Source:

• Ling, Schneider, Peoples, Spoering, Engels, Conlon, Mueller, Schaberle, Hughes, Epstein, Jones, Lazarides, Steadman, Cohen, Felix, Fetterman, Millett, Nitti, Zullo, Chen & Lewis. 2015. A new antibiotic kills pathogens without detectable resistance. Nature.com, http://dx.doi.org/10.1038/nature14098.
• http://phenomena.nationalgeographic.com/2015/01/07/antibiotic-resistance-teixobactin/

So “Once more unto the breach, dear friends, once more;”

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