Anthrax killer: It's sedimentary

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  • Published: Jul 15, 2013
  • Author: David Bradley
  • Channels: X-ray Spectrometry
thumbnail image: Anthrax killer: It's sedimentary

Deadly spores

X-ray crystallography and other techniques have been used to study an unusual antibiotic from a marine actinomycete that has demonstrable efficacy against the lethal microbe anthrax. Centers for Disease Control and Prevention image via Wikipedia

X-ray crystallography and other techniques have been used to study an unusual antibiotic from a marine actinomycete that has demonstrable efficacy against the lethal microbe anthrax.

Anthrax is a potentially lethal infectious disease caused by the spore-forming bacterium Bacillus anthracis and is commonly transmitted by infected farm animals. However, it has also been considered a serious risk as a biological agent in a terrorist attack. Attacks with spore-containing letters caused five deaths in 2001.

Early treatment usually requires a long-winded course of antibiotics and although that can saves lives, more effective, fast-acting antibiotics are needed. Moreover, infection within the respiratory tract does not necessarily succumb to oral drugs and requires continuous intravenous antibiotics, again with mixed outcome. The search for new and effective antibiotics has now become one of some urgency.

Sedimentary search

William Fenical and colleagues at the University of California, San Diego and Trius Therapeutics (San Diego) - Kyoung Hwa Jang, Sang-Jip Nam, Jeffrey Locke, Christopher Kauffman, Deanna Beatty and Lauren Paul - have characterised a new potential anti-anthrax drug from a marine microorganism, a species of Streptomyces found in near-shore sediments from Santa Barbara, California. The culture extracts from this microbe are effective against anthrax itself and several other Gram-positive bacteria, including staphylococci, enterococci, and streptococci. The active compound, which they dubbed anthracimycin, is highly active, the team reports in the journal Angewandte Chemie. A broth microdilution assay against anthrax strain UM23C1-1 showed the compound's minimum inhibitory concentration (MIC) to be 0.031 micrograms per millilitre.

Anthracimycin is a macrolide antibiotic and the researcher's X-ray crystallographic and others studies show that its unusual system of rings - one with fourteen carbon atoms and two with six each - is most likely to be generated by the microbe using the polyketide biosynthetic pathway. The X-ray work also allowed the team to pin down the absolute configurations of the seven asymmetric carbon centres with the molecule thus giving them a complete three-dimensional structure.

Totally tautomeric

The team reports that while their nuclear magnetic resonance (NMR) spectroscopic data could not confirm the presence of a keto-enol tautomerization in the molecule, the X- ray data revealed the enol proton to be disordered but also essentially equidistant between each oxygen atom. This, they say, suggests a rapid keto- enol tautomerization is taking place.

The unusual structure of anthracimycin sets it apart from all other known antibiotics, although a similar carbon skeleton is present in chlorotonil, a metabolite from the terrestrial myxobacterium Sorangium cellulosum. Chlorotonil differs in its carbon skeleton, however, as it contains two chlorine atoms and the stereochemistry of most of its asymmetric carbon centres are unlike those in anthracimycin. The presence of chlorine in that molecule suggested a possible way to change the characteristics of anthracimycin and so the team produced chlorine analogues of their compound. Unfortunately, these turned out to be half as effective against B. anthracis as the original structure.

However, further tests did reveal them to be much more potent in acting against a number of Gram-negative pathogens. It is in the realm of Gram-negative bacteria that most of the bacteria resistant to current antibiotics are to be found, offering an important insight into how to tackle so-called superbugs, such as methicillin, or multiple-resistant Staphylococcus aureus (MRSA). The next step will be to test anthracimycin and analogues, including the chlorinated derivatives initially in animal models and given continued proof of efficacy ultimately in human clinical trials.

Related Links

Angew Chem, 2013, online: "Anthracimycin, a Potent Anthrax Antibiotic from a Marine-Derived Actinomycete"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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