An experimental drug that doesn鈥檛 kill bacteria, instead it transforms them into docile lambs, could be the weapon of choice for the post-antibiotic era.
This approach should forestall drug resistance, which is rendering 鈥溾�� such as penicillin useless for stamping out infection, says , a microbiologist at the University of Texas Southwestern Medical Center in Dallas, who led the development of the new drug.
鈥淲e are getting into a post-antibiotic era with no new ammunition,鈥� she says, pointing to a paucity of new antibiotic drugs developed in recent years. 鈥淭here鈥檚 not going to be one magic bullet out there; however, doing something like this, we are not speeding the process [of antibiotic resistance] too much.鈥�
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Her team鈥檚 proof-of-principle experiment suggests that blocking a bacterium鈥檚 ability to sense human hormones can shut down its infection genes and cripple its ability to kill mice.
However, any test in humans is at least 5 years off, and the actual wait will depend on how the drug fairs in further animal studies, as well as how safe it is. Early indications in mice hint at few side effects.
No signal
The new drug 鈥� dubbed LED209 鈥� prevents bacteria from detecting two hormones key for mounting an infection, epinephrine and norepinephrine (also known as adrenalin and noradrenalin). Without these signals, pathogens such as can鈥檛 churn out toxins or infiltrate animal cells.
When Sperandio鈥檚 team exposed mice to E. coli 0157:H7 or Salmonella, rodents that received the drug before infection fared far better than mice that received no antibiotics. More animals survived, and researchers found fewer bacteria in their organs.
In mice infected with the disease 鈥� a potential bioterror weapon that kills mice and humans 鈥� LED209 did wonders when the researchers administered the drug several hours after infection. Four-fifths of the animals survived tularaemia, whereas just 10% of the untreated mice pulled through.
The drug should also fend off a wide range of bacterial killers. LED209 targets a protein called QseC. Bacteria that cause pneumonia, bubonic plague and several plant diseases have versions of QseC similar to E. coli鈥榮, suggesting that the new drug will hobble them as well, Sperandio says.
And because LED209 doesn鈥檛 kill bacteria, the one bug in a billion that鈥檚 lucky enough to be resistant to the drug won鈥檛 get much of a growth advantage 鈥� the key to antibiotic resistance.
Gentle pressure
鈥淵ou鈥檙e not wiping the other ones out,鈥� she says. 鈥淵ou鈥檙e having a softer evolutionary pressure against resistance.鈥�
鈥淚t鈥檚 an encouraging direction they鈥檙e going in,鈥� says , a microbiologist at Harvard Medical School in Boston. Yet drug resistance might still be possible, as time and time again, bacteria have proved smarter than man-made drugs. 鈥淵ou could slowly build up more and more resistance in the population in a natural setting,鈥� he says.
If LED209 makes it to the clinic, it could work best when paired with a more traditional antibiotic that kills bacteria, Mekalanos says. 鈥淭ry to hit the bug with two punches.鈥�
Sperandio is now working with a small firm, Dallas-based , to speed development.
But she warns that the clinic is a long way off 鈥淚f we鈥檙e lucky and we have a breakthrough, that鈥檇 be great. I鈥檇 rather be conservative.鈥�
Journal reference: (DOI: 10.1126/science.1160354)
