Regulation, biosynthesis and mode of action of formicamycins, promising new antibiotics with a high barrier to resistance

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Most of the antibiotics used in medicine are made from the natural products produced by soil bacteria called Streptomyces, of which there are thousands of different strains. They were discovered during a golden age of antibiotic discovery between 1940 and 1960. By the 1960s, however, scientists began to rediscover the same species, making the same, known compounds. They gave up searching for new compounds because they thought they had found all the natural antibiotics. In fact, they only discovered the easy to find strains and antibiotics, the so-called low hanging fruit.Everything changed in 2000 with the sequencing of bacterial genomes. A genome contains all the instructions for the life of the cell, and by reading the instructions for thousands of Streptomyces strains we now know these bacteria have instructions for many more antibiotics than they make in the lab. This means we have only discovered a small proportion of the antibiotics made by these bacteria in their natural habitats. This is good news because we must discover and develop new antibiotics to tackle an alarming number of drug resistant infections. Bacteria can adapt quickly and rapidly become resistant to antibiotics which means most of the antibiotics we previously discovered are no longer working. This is known as AntiMicrobial Resistance (AMR) and the UK government predicts that if we fail to tackle AMR now we will face 'Antibiotic Armageddon' by the 2050s - that antibiotics will no longer be effective and infectious diseases will become a bigger killer than cancer, causing around 10 million deaths worldwide every year. Ten priority areas of action have been suggested, including increasing public awareness and stimulating early stage antibiotic discover, both of which are covered by our project proposal.To discover new antibiotics, we use genome mining, which means sequencing Streptomyces genomes and then looking for sets of instructions (biosynthetic gene clusters) to make new antibiotics that we haven't seen before. We find and sequence new Streptomyces strains living on insects or in plant roots and we manipulate these bacteria to switch on production of their antibiotics, e.g. by genetically engineering the strains to over-express the biosynthetic genes. We are searching in these environments because they have been previously overlooked, and because there is evidence that Streptomyces strains from these environments have an increased potential for producing new antibiotics.Our research also allows us to make lots of any new antibiotic, so we can purify it, determine its activity and figure out how it kills bacteria (targets and mechanism of action). This information is essential if the antibiotics are to be developed as drugs. It is also essential to understand how the producing strain is resistant to the antibiotics (which it must be, to avoid suicide) and whether disease causing bacteria can acquire resistance easily. Antibiotics which are easily resisted are not desirable as drug candidates but sometimes we can modify them and make semi-synthetic antibiotics which are more effective.We used genome mining to identify a new group of antibiotics called formicamycins. They have powerful activity against Gram-positive superbugs like MRSA and VRE and they do not become resistant to formicamycins in the lab. We are working with a synthetic chemist to make new versions that target harder to kill Gram-negative bacteria like E. coli. We also identified the biosynthetic gene cluster and now we need to understand how the genes are regulated and to identify the natural resistance genes. We will use this knowledge to engineer strains to over-produce formicamycins and intermediates in its biosynthesis. Then we will purify large amounts of the molecules for semi-synthesis and to determine targets and modes of action and resistance in disease-causing bacteria. These are essential first steps in determining whether they are good drug candidates.