Fri. Feb 3rd, 2023
Learning the rules of antibiotics to make old drugs work on new bugs

Bacteria come in two flavors: gram-positive and gram-negative. Gram is a violet dye, named after its discoverer, that is more easily absorbed by some microbes (the Gram-positive) than others (you guessed it, the Gram-negative). Gram negative bacteria are surrounded by two cell membranes and the outer one is very difficult to cross. This outer membrane not only keeps out the Gram dye, but also many commonly used antibiotics.

We not only urgently need new antibiotics, but also new types of antibiotics. The latest new class of antibiotics effective against Gram-negative bacteria, including those that cause whooping cough, Legionnaires’ disease, typhoid fever and bubonic plague, was last introduced in 1968. And that’s not for lack of effort. In 2007, GlaxoSmithKline reported that 500,000 compounds were screened for activity against E coli and came up with a grand total of none.

Now a team of researchers may have figured out a way to get antibiotics that don’t normally work on Gram-negative bacteria in those cells. Once in, the antibiotics seem to be just as effective as drugs specific to Gram-negative bacteria.

Part of the problem was that we don’t really know what makes an antibiotic effective against Gram-negative bacteria. Retrospective analysis of antibiotics that do work suggests that the antibiotics must be quite small and quite polar, meaning they must have regions on the molecule that carry a light charge. This makes sense because they must enter the cell through tiny, polar channels called “porins.”

But many small, polar antibiotics don’t get in, so those can’t be the only requirements. To generate a set of rules that can be used to create antibiotics that target Gram-negative bacteria, the team screened 180 different chemicals for their ability to penetrate. E coli.

Charging makes all the difference

Researchers on the team found that a positive charge is the main determinant of whether a molecule gets into it E coli. Twelve of the 41 positively charged molecules they tried got in; zero neutral or negatively charged molecules did. All 12 had an amine group (which has a positively charged nitrogen), which is important but insufficient for accumulation. The flexibility and shape of the molecule also mattered; more rigid, flatter (as opposed to rounder) molecules came in E coli easier. Despite the importance of charge, some of the charge-free surface also seemed necessary.

The importance of the amine had been noted before and other scientists have attempted to convert Gram-positive antibiotics into Gram-negative active antibiotics by adding an amine. It often didn’t work, possibly because the starting molecule didn’t have the right flexibility and shape. In this newer work, the researchers focused on a drug that had the right shape and flexibility, and they managed to convert a drug that is only gram-positive into a broad-spectrum antibiotic by adding an amine. Their new molecule retained activity Staphylococcus aureusa gram-positive bacterium, and became active against four of the five gram-negative pathogens, including a multidrug-resistant strain.

The authors hope that this set of rules — molecules must be positively charged, contain an amine group, and be rigid and non-spherical — will boost the conversion of other gram-positive antibacterials into broad-spectrum drugs. They also suggest that knowing these rules could aid in the synthesis of new compounds specific to Gram-negative bacteria. This latter route could become necessary, as amines are quite rare in natural compounds and are “vanishingly rare” in the standard collections of chemicals screened for drug activity.

Nature2017. DOI: 10.1038/nature22308 (About DOIs).

By akfire1

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