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New Method Profiles Microbe Structure in the Search for Novel Antibiotics

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    Traditional methods scientists have employed while on the hunt for better antimicrobial compounds have proven effective, yet extremely time-consuming and inefficient, often yielding only a few candidate compounds to take further into clinical studies. However now, researchers at UC San Diego have developed a method they believe will help identify and characterize new antibiotics, as well as be utilized to screen natural products quickly for compounds capable of controlling antibiotic-resistant bacteria.


    The investigators have confidence that their discovery will allow chemists and others to understand how mixtures of potential antibiotics from microorganisms work without first purifying them. Their current work builds upon previous work from their laboratory where the research team developed a novel process for rapidly identifying new compounds capable of killing bacteria.


    “Our initial discovery allowed us to perform the equivalent of an autopsy on bacterial cells and is changing the way industry searches for new antibiotics from collections of pure chemicals,” explained senior author Kit Pogliano, Ph.D., professor of biology at UCSD. “But we didn’t know if it would work for identifying antibiotics found in natural product extracts, which are very complex mixtures frequently filled with multiple types of antibiotics.”


    “We’ve now shown that our method is a powerful way to identify antibiotics from natural products and understand how they work before they are ever purified,” Dr. Kit Pogliano added, “potentially shaving years off of screening efforts by identifying which organisms and growth conditions produce interesting bioactive molecules.”


    The findings from this study were published recently in the Journal of Antibiotics through an article entitled “Application of bacterial cytological profiling to crude natural product extracts reveals the antibacterial arsenal of Bacillus subtilis.”


    Many traditional methods for isolating natural product antibiotics are slow since it is often requisite that molecules be purified before performing extensive experiments to determine how they work and if they are efficacious.


    “This is a very slow, labor-intensive process that typically requires many months of effort, and frequently ends with discovering that the molecule does not have a new or interesting mechanism of action,” noted co-author Joe Pogliano, Ph.D., professor of biology at UCSD. “Our method solves this problem by providing a new way to find a unique needle in a haystack of needles. Before any of the time-intensive work has been started, we can determine which samples have an activity that is new or interesting.”


    In the past two decades the number of new antibiotics entering the clinic has drastically declined, while, in the same timeframe, many bacteria have evolved resistance to all of the currently available drugs. The main problem with identifying new antibiotics and bringing them to market is a lack of understanding how the molecules work.


    “It’s easy to identify microbes that produce antibiotics that kill bacteria,” Dr. Kit Pogliano explained. “The difficult part is determining which microbes produce a new molecule with a new activity. With our new method, we can determine which strain is producing an interesting activity and then follow that specific activity during purification to make sure we purify the right molecule. This new approach will help to open up the discovery pipeline, allowing more potential antibiotic producing strains to be rapidly screened for antibiotics that are active against multidrug resistant bacterial pathogens.”


    The investigators used a method of bacterial cytological profiling (BCP) to rapidly determine the mechanism of action for various compounds in complex natural product extracts.


    “We prepared an extract from Bacillus subtilis 3610 that killed the Escherichia coli lptD mutant and used BCP to observe two types of bioactivities in the unfractionated extract: inhibition of translation and permeabilization of the cytoplasmic membrane,” stated the authors. “Thus, BCP simplifies the isolation of novel natural products, by identifying strains, crude extracts, and fractions with interesting bioactivities even when multiple activities are present, allowing investigators to focus labor-intensive steps on those with desired activities.”


    The researchers were energized by their findings and were continuing the search for potential new therapies to stem the tide of the rapid rise in drug-resistant microbes.


    “We are now using this method to look for new antibiotics from unique collections of microbes to find those that are active against antibiotic resistant bacteria,” Dr. Kit Pogliano said.

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