Scientists modify toxic pesticide to treat antibiotic-resistant bacteria

A significant class of heterocyclic compounds, called N-Aryl-C-nitroazoles, is used as fungicides and pesticides. But these substances could be harmful to human beings and cause mutations.

Since these compounds are not commonly used, there is not much information about them in the medicinal chemistry literature. But recently it has been indicated that the class of compounds that are conventionally avoided can help combat pathogenic bacteria.

However, to minimize the harmful effects, a large amount of work must be performed at the molecular level, that is, precise optimization of the molecular environment of the nitro-heteroaromatic “warhead”. The feasibility of this method was shown in the early 2000s through the development of pretomanid and delamanid, which are both anti-tuberculosis medications presently approved for medical use.

These medications serve like prodrugs, that is, the substance itself is not active but still acquires novel properties upon penetrating the human body.

With respect to this study, researchers from the Baltic Federal University along with collaborators from St. Petersburg State University, the L. Pasteur Research Institute of Epidemiology and Microbiology, and the Research Institute of Phthisiopulmonology in St. Petersburg, are searching for new effective antibacterial medications, examining numerous nitrogen heteroaromatic compounds with a nitro group, which could be further used in medicine.

The team found that the compound, called OTB-021, performs well against drug-sensitive strains of tuberculosis bacteria but was inefficient against pathogen strains belonging to the supposed ESKAPE panel.

ESKAPE is a short form used for the names of bacterial species—Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter aerogenes—that usually develop resistance to antibiotic drugs. ESKAPE is a kind of a pun: “eskape” sounds like “escape”, and the microbes of this panel are said to be resistant to a majority of the familiar antibiotics, that is, they appear to “escape” from drugs.

The team built two isomeric (identical in the atomic arrangement) series on the basis of the OTB-021 to interpret how to change this compound so that it could act on such pathogenic bacteria. Side amino groups modified their position to render the aromatic nitrogen-rich core of the substance more compact, this should decrease the substance toxicity.

The team tested the microorganisms’ sensitivity to a new compound through a disk diffusion technique and then measured the inhibition zones of bacterial growth using antibiotic disks and a dried solution of the compound in Petri dishes.

But it turned out that the new substances easily suppressed the ESKAPE bacteria. The minimal chemical concentration that blocks the bacterial growth (μg/ml) for the evaluated substance demonstrated a result similar to the use of an ml of the antibiotic ciprofloxacin: for instance, 0.3 μg/mL of an antibiotic for Enterococcus serves the same as 2 μg/mL of one of the novel substances.

Starting from the structure of the antimycobacterial OTB-021 which has no activity against ESKAPE pathogens, we developed, synthesized, and tested two isomeric series of novel analogs with an amino group that changes its position in the structure.”

Mikhail Krasavin, Doctor of Chemical Science and Professor, Russian Academy of Sciences

Krasavin is also a professor and researcher at the Immanuel Kant Baltic Federal University.

These compounds can inhibit the growth of all ESKAPE pathogens. Probably, they will help to develop new effective drugs against bacterial diseases which are sometimes very difficult to treat.”

Mikhail Krasavin, Doctor of Chemical Science and Professor, Russian Academy of Sciences

Source:
Journal reference:

Chuprun, S., et al. (2020) Mutually Isomeric 2- and 4-(3-Nitro-1, 2, 4-triazol-1-yl) pyrimidines Inspired by an Antimycobacterial Screening Hit: Synthesis and Biological Activity against the ESKAPE Panel of Pathogens. Antibiotics. doi.org/10.3390/antibiotics9100666.

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