iChip based discovery of a potent novel antibiotic
Why do we need a new antibiotic?
What can happen if you self-medicate on an antibiotic or do not finish a course of antibiotics that has been prescribed for you? When cattle are fed indiscriminately on antibiotics to keep them healthy? When sewage from hospitals is not completely treated and released into the community? The microbes that survive in these environments stop responding to antibiotics around them (1). Our world at present faces a daunting task of treating people infected with resistant forms of many bacteria. Often clinicians have to resort to potent broad spectrum antibiotics to treat infections that could be treated with the first line of drugs a few decades ago. The other aspect of the problem of antimicrobial resistance is the lack of new treatment options. Many of the current antibiotics are chemical modifications of ones that are known to work. Designing completely novel molecules, with antibiotic activity, synthetically, has not been very successful (2). In this rather bleak situation a new study brings a new ray of hope. In this study the authors have enriched hitherto uncultivated bacteria from the soil (3).
What is so special about this?
A very small percentage of bacteria in the soil can actually be grown in the laboratory (4). The development of tools/methods to grow more bacteria opens up a window for isolating new compounds with potential antimicrobial activities that these bacteria may be producing to their advantage in the complex niche of the soil. In this study, the authors diluted soil sample to contain single cells and grew them in special chambers embedded in the soil which allow for nutrient exchange with the soil. Earlier studies have shown this method to recover 50% of the bacteria from the soil. Previous studies have also demonstrated that once isolated, many of these bacteria can be grown in the lab.
How was this antibiotic found?
After screening over 10000 bacterial isolates in this way Ling et al., identified a new species Eleftheria terrae that produced a potent compound against Staphylococcus aureus (S. aureus can cause infections especially in hospitals, it also notorious for acquiring resistance to commonly used antibiotics). They examined this compound in greater detail, asking questions like- what does it look like (chemical structure)? How is it made in the bacteria (biosynthetic pathway)? To answer these questions, they undertook detailed chemical analysis by NMR and Marfeys’ structure analysis. The active compound which the authors named Teixobactin, was found to be a uricylated oligopeptide (the details of the structure are provided in the paper). They analyzed and were able to predict the pathway by which the E. terrae makes this antibiotic. The compound was found to be completely novel.
How does it work?
How does this antibiotic kill the target bacteria? The first clue was that it was more effective against gram positive that gram negative bacteria. These two classes (distinguished on the basis of their appearance after staining them with dyes) of bacteria differ in the number and nature of protective coverings around them. Gram positive bacteria have a thick cell wall around them, whereas gram negative bacteria have a thin cell wall but also have an additional outer membrane. The cell wall is made up of repeating units of modified sugars known as peptidoglycan and is essential for structural integrity of bacteria. A breach in this structure would lead to the bacterium’s death. Interestingly, Teixobactin is not active against gram negative bacteria which have an outer membrane. However, a strain of E coli (a gram negative bacteria) with defects in the outer membrane is susceptible to this antibiotic. These data suggest that Teixobactin needs to have access to the bacterial cell wall for its activity. Consistent with this idea, they find that Teixobactin binds specifically to precursors of peptidoglycan and does not allow their incorporation into the cell wall. Instead of targeting the enzymes that carry out cell wall synthesis, Teixobactin, like the potent antibiotic, Vancomycin, interacts with structural components of the cell wall itself. It seems to target multiple precursors and bacteria die not only from lack of cell wall but also from accumulation of toxic intermediates of cell wall synthesis.
Does it work against pathogens?
They then asked, how effective is this antibiotic against common pathogens? Teixobactin was found to have potent activity against Staphylococcus aureus (which can cause disease under certain circumstances), Clostridium difficile (causes colitis) and Bacillus anthracis (anthrax). It also had good activity against hard to treat microorganisms like Mycobacterium tuberculosis (Tuberculosis) and enteroccocci (are intrinsically antibiotic resistant, causally associated with urinary tract infection among others). All of this is good news, however, how do we know that once in use, bacteria will not become resistant to Teixobactin? One way to answer this question is to subject bacteria to low levels of the antibiotic for prolonged period and then test if they still respond to it. Fortunately, no resistance to Teixobactin emerged in either M tuberculosis (M Tuberculosis is notorious for acquiring resistance to multiple drugs) (6) or S aureus. Suggesting that resistance will probably be slow to evolve against this antibiotic. The next step then was to assess if it was toxic to animal cells and/ or effective when used in animals.
The compound was found to be eminently suited for being used as a drug in animals. It was not toxic to mammalian cells, was active even in the presence of serum and was stable in blood. Moreover, Teixobactin seems to have no carcinogenic properties. In mouse models of septicemia and pneumonia, mice treated with Teixobactin survived and responded well to treatment. This makes Teixobactin a remarkable candidate for further studies with the possibility of clinical trials in humans.
What does this finding mean?
The approach used to isolate and characterize Teixobactin is novel and paves way for the identification and characterization of many such compounds. We think that this may well be the beginning of a mining exercise where we explore more antimicrobials from the soil. It remains to be seen if Teixobactin can actually be used in humans, it is unclear how long that will take or last. At the very least, Teixobactin offers a tempting glimpse of what’s hidden in the soil and gives us a better appreciation for the microbial community we nonchalantly read upon.
2. “Challenges of Antibacterial Discovery”, Lynn L. Silver Clin Microbiol Rev. 2011
3. “A new antibiotic kills pathogens without detectable resistance.” Losee L. Ling et al., Nature 2015
4. “Cloning the soil metagenome: a strategy for accessing the genetic and functional diversity of uncultured microorganisms.” Michelle R. Rondon Appl Environ Microbiol. 2000
5. “Short peptide induces an “uncultivable” microorganism to grow in vitro.” D. Nichols Appl Environ Microbiol. 2008