Source: https://www.nature.com/articles/s41564-018-0110-1 Culture-independent discovery of the malacidins as calcium-dependent antibiotics with activity against multidrug-resistant Gram-positive pathogens Despite the wide availability of antibiotics, infectious diseases remain a leading cause of death worldwide1. In the absence of new therapies, mortality rates due to untreatable infections are predicted to rise more than tenfold by 2050. Natural products (NPs) made by cultured bacteria have been a major source of clinically useful antibiotics. In spite of decades of productivity, the use of bacteria in the search for new antibiotics was largely abandoned due to high rediscovery rates2,3. As only a fraction of bacterial diversity is regularly cultivated in the laboratory and just a fraction of the chemistries encoded by cultured bacteria are detected in fermentation experiments, most bacterial NPs remain hidden in the global microbiome. In an effort to access these hidden NPs, we have developed a culture-independent NP discovery platform that involves sequencing, bioinformatic analysis and heterologous expression of biosynthetic gene clusters captured on DNA extracted from environmental samples. Here, we describe the application of this platform to the discovery of the malacidins, a distinctive class of antibiotics that are commonly encoded in soil microbiomes but have never been reported in culture-based NP discovery efforts. The malacidins are active against multidrug-resistant pathogens, sterilize methicillin-resistant Staphylococcus aureus skin infections in an animal wound model and did not select for resistance under our laboratory conditions. What a clever approach if I understand it correctly. Having identified a genetic sequence associated with cell wall formation or attack, they used DNA amplification to search for sequences having a similar structure. Very clever as it uses one piece of knowledge about DNA structures associated with what is desired; amplified, and; tested to see if it attacks the bacteria and not the host. Bob Wilson
Fast scanned through the post. Saw the figure. Dang, Bob! Half second later I realized that they drew it, not you. This is an excellent example of visual communication in science. As people now think it should be done. Article no doubt makes it clear that microbial warfare in soils (and other decomposition environments) has probably evolved a large proportion of effective anti-microbial chemicals. In other words, if it can possibly work, somebody does it in some soil somewhere. And there's more Not just the chemical is there, but the underlying genetic sequence that allows ribosomal construction of the chemical. Humans arrived very late to ongoing global microbial warfare. Now learning how to read the book.
As article makes clear, most microbes living in soils cannot be cultivated. They took a clever but somewhat limiting sidestep. They used a short genetic sequence already known to code for calcium-dependent antibiotics and looked for that in the wild. So, they would not find anything lacking that sequence. Broadening that (as may be done in Discussion; have not yet read). Look for any genetic tag representing any drug class. In other words, do this same thing again for all recognized drug classes. They rely on a library of global soils selected for drug development. There is another independent library dedicated solely to figuring out microbial diversity. I am sure authors know of that...
amazing. my mother in law lived 5 years, after docs told her there were no more abx that would help her uti.
It is amazing. For at least 400 million years terrestrial microbes have been releasing 'digestive' enzymes to their local environments. Products of those enzymes diffuse wherever, not necessarily back to the cell that 'paid for' lunch. Cheaters can prosper. And so the longest war began. From a conservative generation time of 1 week we can suggest 28 billion generations of microbes have been tinkering with offense and defense. That is a lot. This big book has already been written. Early days of people learning to read it.
Their Figure 4 is lovely as well. Cell membranes have many highly specific transfer channels. Messing one up is common mode of action for antibiotics and other toxins. Recently elsewhere we talked about pufferfish in this context. Many other examples are known. And unknown, one might suppose
Exciting discovery here with this novel culture-independent approach. Although it is possible malacidins may eventually become therapeutic options, most antibiotics that show promise at this stage end up being too toxic for human therapy. For this particular class of antibiotics there remains a lot more work to be done to show that they are safe and efficacious. They discuss doing some basic mammalian cytotoxicity assays - "the malacidins showed no significant toxicity or haemolytic activity against mammalian cells at the highest concentrations tested", but this is just the beginning of toxicity testing. Stable systemic delivery methods would also have to be validated. Their animal model deals with the topical treatment of a deep skin infection. To be clinically useful it would have to be stable in IV form, have low systemic and organ toxicity over weeks of treatment, and have good organ bioavailability. Specifically, the main clinical use for these would likely be for vancomycin resistant deep tissue infections like osteomyelitis (bone infection) and endocarditis (heart valve infection). But even if 9 out of 10 times is a strike out, this new approach will allow us to "roll the dice" that much more that the chance of eventually turning up something clinically useful is greatly enhanced.
I have forgotten who and where I learned of it, but I had used a little soil sample kit sent out by such a group of researchers.
