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Drug-resistant bacteria tricked into dropping their shields become vulnerable once again

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Bait-and-switch might just be the oldest trick in the book, but maybe it’s time to start kickin’ it old school. At least a little bit. In search of another way to manage the endless slog against antibiotic-resistant bacteria, scientists just figured out how to bait bacteria into developing an Achilles’ heel.

Not all drug resistance works the same: It depends on the type of antibiotic the bacteria have evolved to resist. Some antibiotics do their work by impeding bacterial cell division. Others, like the -cillins, disrupt cell walls. Drugs like -cyclines and -mycins interfere with protein production, which brings the whole cell abruptly to a stop. Some drugs are bacteriostatic, which means they stop bacteria from dividing, while others are bacteriocidal: they actually kill live cells. It’s just a question of where in the reproductive process do we kill the microbes.

Selective pressure is a strange and subtle thing. Bacteria still have to deal with scarcity, even on their scale, and making proteins is expensive. Antibiotic resistance genes are expensive, the authors argue, because making those proteins imposes a “substantial fitness costs.” It’s sort of like a flak jacket. It’s hot and clumsy and even though it’s saving your life, you want to take it off once there’s no shooting going on.

When resources are scarce and selective pressure is strong, mutations become more frequent. During the normal course of cell division, a bacterium can sort of ditch the more expensive plasmids they’ve been keeping around, leaving only those cells alive that can handle the scarcity. Those lottery winners go on to reproduce with their newly streamlined genome.

In just the same way, bacteria tend to play it fast and loose with genes. They often participate in lateral gene transfer, which is more or less one microbe extending a cytoskeletal shiv and shaking down neighboring microbes for plasmids or transposons. Sometimes, though, the plasmid thieves get more than they bargained for: Some genes make bacteria immune to one drug, but just because they have the sequence they do, they make the bacteria susceptible to another drug. This is called collateral sensitivity, and it’s the key to these scientists’ approach.

It’s like a combination of a shiv and a straw. Image: Charles Brinton, via NIH

First they isolated a strain of E. coli, which is an omnipresent gut flora among other things. This particular strain had acquired a gene for resistance to tetracycline (tet) on a transposon — a segment of DNA that can hop around the genome. It codes for a thing called an efflux pump, which pumps tetracycline right out of the bacterium whenever a molecule of tet comes near. As it happens, that transposon also makes it collaterally sensitive to two other drugs: disulfiram (Antabuse), and a known antimicrobial compound called β-Thujaplicin, isolated from the red cedar and other trees in the cypress family.

Soaking a tet-resistant population of E. coli in β-Thujaplicin hit the bacteria in their efflux-pump Achilles’ heel. The bacteria quickly dumped their tet-resistance transposon. Doxycycline finished them off without so much as a murmur.

Stone et al, 2016

Since tet resistance is so common, -cyclines are often practically useless in the field. This experiment wasn’t a TKO: The researchers identified a single bacterium, one microbe, that had a frameshift mutation which could have rendered it resistant to both tetracycline and β-Thujaplicin. That means, like every therapy, that it isn’t a magic bullet for defeating antibiotic resistance. But it’s a start; it’s an avenue to explore. The authors remark that “two-phase treatments [like this] that counteract the evolutionary advantage of resistance could add valuable tools to our antimicrobial arsenal.”



[Source:- Extremetech]


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