Tag: metagenomics

  • New Age Bioprospecting for Antimicrobials

    One of the major contributors to improved healthcare outcomes and reduced mortality in the post-World War II era was the widespread use of antibiotics. Able to treat infection, these miracle drugs literally transformed bacteria from humanity’s primary killer to a manageable problem.

    But, in recent decades, the decline in the discovery of novel antibacterials (and other antimicrobials like antifungals) and the rapid rise in antimicrobial resistance has threatened this happy state. This has led many experts to worry about what will happen in a post-antibiotic world. After all, without effective antibiotics, we not only lose the ability to treat life-threatening diseases like tuberculosis (not to mention common ailments which are a nuisance today but may become more serious like strep throat, urinary tract infections, and ear infections), but we will also lose the ability to perform many surgeries safely (as recovery oftentimes counts on antibiotics to prevent and hold at bay infections).

    While we need to get smarter about how and where we use antibiotics (especially in agricultural applications) to slow the rise of resistance, the other half of this problem is in discovering and commercializing new antimicrobials. This is something we’ve largely failed to do since the 1960s, as the figure below from the C&EN article derived from data in a 2019 paper shows.

    The “golden age” of antimicrobial discovery that ended in the 1960s came largely from researchers searching for these miracle chemicals in soil samples (“bioprospecting”), where bacteria and fungi, in order to compete, release them as “chemical weapons” against others. But, having long ago exhausted the “easy” antimicrobials, we were unable to replicate this success in the decades following the 1960s

    But maybe this is about to change. In March, two completely new classes of antimicrobial were published in two weeks (both in Nature) — equaling the total output of the 2010s! Both papers (one by a group from China Pharmaceutical University in Nanjing, China and the other from a collaboration between University of Illinois in Chicago and McMaster University in Canada) were centered around identifying biosynthetic gene clusters (BGCs) responsible, and with the lower cost of metagenomic sequencing and new computational methods, this may point to a new era of discovering novel antimicrobials to help us innovate our way out of our current antimicrobial resistance dilemma by re-inventing bioprospecting.

    A good reminder that what we need is the political and scientific willpower to keep funding this type of research and the types of genomic and protein databases that make this type of innovation possible!

    In March, the journal Nature published the discoveries of two paradigm-breaking antimicrobial compounds in as many weeks: a polyene macrolide antifungal called mandimycin and a lasso peptide antibiotic called lariocidin.

    Both these compounds, which use never-before-seen antimicrobial mechanisms, were found using techniques that let researchers look deep into the chemical diversity of microbes—much deeper than a typical antibiotic or antifungal screen might go. And it’s not just these two molecules. Scientists are using the new approaches to discover countless other antimicrobial compounds with the potential to become drugs.

    Bioprospectors mine microbial genomes for antibiotic gold
    Max Barnhart | C&EN

  • Fat Flora

    Source: Healthy Soul

    November’s paper was published in Nature in 2006, and covers a topic I’ve become increasingly interested in: the impact of the bacteria that have colonized our bodies on our health (something I’ve blogged about here and here).

    The idea that our bodies are, in some ways, more bacteria than human (there are 10x more gut bacteria – or flora — than human cells on our bodies) and that those bacteria can play a key role on our health is not only mind-blowing, it opens up another potential area for medical/life sciences research and future medicines/treatments.

    In the paper, a genetics team from Washington University in St. Louis explored a very basic question: are the gut bacteria from obese individuals different from those from non-obese individuals? To study the question, they performed two types of analyses on a set of mice with a genetic defect leading to an inability of the mice to “feel full” (and hence likely to become obese) and genetically similar mice lacking that defect (the s0-called “wild type” control).

    The first was a series of genetic experiments comparing the bacteria found within the gut of obese mice with those from the gut of “wild-type” mice (this sort of comparison is something the field calls metagenomics). In doing so, the researchers noticed a number of key differences in the “genetic fingerprint” of the two sets of gut bacteria, especially in the genes involved in metabolism.

    Source: Figure 3, Turnbaugh et al.

    But, what did that mean to the overall health of the animal? To answer that question, the researchers did a number of experiments, two of which I will talk about below. First, they did a very simple chemical analysis (see figure 3b to the left) comparing the “leftover energy” in the waste (aka poop) of the obese mice to the waste of wild-type mice (and, yes, all of this was controlled for the amount of waste/poop). Lo and behold, the obese mice (the white bar) seemed to have gut bacteria which were significantly better at pulling calories out of the food, leaving less “leftover energy”.

    Source: Figure 3, Turnbaugh et al.

    While an interesting result, especially when thinking about some of the causes and effects of obesity, a skeptic might look at that data and say that its inconclusive about the role of gut bacteria in obesity – after all, obese mice could have all sorts of other changes which make them more efficient at pulling energy out of food. To address that, the researchers did a very elegant experiment involving fecal transplant: that’s right, colonize one mouse with the bacteria from another mouse (by transferring poop). The figure to the right (figure 3c) shows the results of the experiment. After two weeks, despite starting out at about the same weight and eating similar amounts of the same food, wild type mice that received bacteria from other wild type mice showed an increase in body fat of about 27%, whereas the wild type mice that received bacteria from the obese mice showed an increase of about 47%! Clearly, gut bacteria in obese mice are playing a key role in calorie uptake!

    In terms of areas of improvement, my main complaint about this study is just that it doesn’t go far enough. The paper never gets too deep on what exactly were the bacteria in each sample and we didn’t really get a sense of the real variation: how much do bacteria vary from mouse to mouse? Is it the completely different bacteria? Is it the same bacteria but different numbers? Is it the same bacteria but they’re each functioning differently? Do two obese mice have the same bacteria? What about a mouse that isn’t quite obese but not quite wild-type either? Furthermore, the paper doesn’t show us what happens if an obese mouse has its bacteria replaced with the bacteria from a wild-type mouse. These are all interesting questions that would really help researchers and doctors understand what is happening.

    But, despite all of that, this was a very interesting finding and has major implications for doctors and researchers in thinking about how our complicated flora impact and are impacted by our health.

    Paper: Turnbaugh et al., “An obesity-associated gut microbiome with increased capacity for energy harvest.” Nature (444). 21/28 Dec 2006. doi:10.1038/nature05414

    Check out my other academic paper walkthroughs/summaries