Antibiotics from the microbial dark matter

Our ability to discover novel compounds has diminished, and pathogens acquire and spread resistance largely unchecked, leading to a human health crisis. The main source of antibiotics – soil actinomycetes – has been overmined. The problem is compounded by the presence of dormant persister cells tolerant to killing by all antibiotics. As a result, chronic osteomyelitis or infections of patients with cystic fibrosis can be untreatable. There are then two main problems facing the field of antibiotic discovery – resistance; and tolerance. Ideally, we need compounds free of resistance; and antimicrobials capable of killing dormant cells with inactive targets. We reasoned that antibiotic producers face similar problems that we do, and evolved anti‐persister compounds. We considered an old abandoned antimicrobial acyldepsipeptide (ADEP) as a possible anti‐persister antibiotic. The compound targets the ClpP/A,C,X protease which normally degrades misfolded peptides with the aid of its ATP‐dependent chaperones. In the presence of ADEP the chaperones are no longer needed. We found that ADEP causes massive degradation of mature proteins in S. aureus by the disregulated ClpP protease, killing persisters both in vitro and in a biofilm model of infection in a mouse. In search of new antibiotics, we decided to target uncultured microorganisms, which make up 99% of the total diversity. We developed approaches to grow uncultured bacteria and find that this “microbial dark matter” harbors novel antimicrobials. Lassomycin produced by soil actinomycetes kills persisters of Mycobacteria by forcing the ClpC1 chaperone to hydrolyze ATP. Teixobactin, made by a β‐proteobacterium, is essentially free of resistance. It binds two immutable targets, lipid II and lipid III. These examples suggest that natural products that can address the dual problem of resistance and tolerance were evolved by producing microorganisms, and mining uncultured bacteria holds the promise of reviving the field of antibiotic discovery. Support or Funding Information T‐RO1 AI085585, Bill & Melinda Gates Foundation