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Modified Antibiotics to Combat Gram-Negative Bacterial Defenses

Modified Antibiotics to Combat Gram-Negative Bacterial Defenses

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  • Antibiotics could increase the risk of drug-resistant microbes thereby making the treatment difficult.
  • Scientists have succeeded in modifying antibiotics to overcome gram-negative bacterial defenses.
  • Deoxynybomycin (DNM) antibiotic is modified by adding an amine group to 6-DNM amine, made fairly rigid and flat to fight against gram-negative bacteria.

A drug that kills only gram-positive bacteria has been modified by a research team from the University of Illinois to develop antibiotics that are increasingly drug-resistant microbes.

The study findings appear in the journal Nature.


Modified Antibiotics to Combat Gram-Negative Bacterial Defenses

The research team had done modifications so that the drug could also kill the gram-negatives. This includes strains of Escherichia coli, Acinetobacter, Klebsiella and Pseudomonas aeruginosa which are becoming increasingly resistant to the gram negative bacteria according to the Centers for Disease Control and Prevention.

Paul Hergenrother, Professor, University of Illinois, said that the efforts to develop new drugs have continuously failed because all the drugs are unable to penetrate the gram-negative bacterial cell wall.

"We have a handful of classes of antibiotics that work against gram-negatives, but the last class was introduced 50 years ago, in 1968."

"Now, the bacteria are developing resistance to all of them."

The scientists have also said that around 500,000 compounds for activity against E.coli was tested by a large pharmaceutical company. And none of which had led to the development of a drug.

Hergenrother said, "These microbes have an outer membrane that is basically impermeable to antibiotics or would-be antibiotics."

"Any drugs that work against them almost always are going through a special gateway, called a porin, that lets in amino acids and other compounds the bacteria need to live."

Instead of using commercial chemical libraries, the research team had created a collection of complex molecules. These include some of the natural products of plants and microbes that were modified.

Hergenrother said, "A few years ago, we found that through a series of organic chemistry steps we could change natural products into molecules that look very different from the parent compounds."

The developed new molecules are more diverse than most compounds available commercially. The research team also produced more than 600 compounds using the new approach.

The researchers tested the compounds individually against the gram-negative bacteria and looked out for those that successfully accumulated inside the cells.

Hergenrother said, "The few that got in all had amines on them, so we started building out from there."

Amines contain molecular components which in turn contain nitrogen. The research team also tested more compounds with amines and the success rate increased.

Hergenrother said, "Having an amine was necessary but not sufficient."

Three Key Traits
The research team discovered three key traits using a computational approach:
  • Compound should have an amine group that is affected by molecular compounds
  • It must be fairly rigid (floppy compounds are likely to get stuck in the porin gateway)
  • It must have low globularity ( should be flat not fat)
Testing the Guidelines
In order to test the three key traits, the research team decided to add an amine group to the deoxynybomycin compound that was created in the 1960s by Kenneth Rinehart Jr.

Deoxynybomycin compound was chosen because it is a potent killer of gram-positive bacteria and also has other desirable traits.

Adding an amine group will also convert deoxynybomycin (DNM) to a 6-DNM amine.

Hergenrother said, "The point is not necessarily this compound, which may or may not be a good candidate as a drug used in human health."

"It's more important as a demonstration that we understand the fundamentals at play here. Now, we know how to make collections of compounds where everything gets in."

Compounds that would penetrate the membrane is important and also the antibiotics must kill the bacteria. Previous research also suggests that one in 200 compounds are capable of penetrating and killing the bacteria.

Hergenrother said, "These are workable odds, Much better than zero in 500,000."

  1. Michelle F. Richter et al, Predictive compound accumulation rules yield a broad-spectrum antibiotic, Nature (2017); DOI: 10.1038/nature22308

Source: Medindia

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