Editors' ChoiceAntibiotics

Looking at the 99% in nature to stop drug-resistant bacteria

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Science Translational Medicine  11 Feb 2015:
Vol. 7, Issue 274, pp. 274ec25
DOI: 10.1126/scitranslmed.aaa8313

Modern medicine has saved many lives because of the advent of antibiotics to treat severe infections. Over 20 classes of antibiotics were discovered before the 1960s, but only a handful have been discovered in the past four decades. This shortage of new drugs has contributed to the rapid development of resistance to existing antibiotics, a problem that is epidemic in proportions. Thus, there is a great need for new antibiotics and for antibiotics that can fight against drug-resistant “superbugs.” Historically, most antibiotics were discovered as a result of screening soil microorganisms. However, only 1% of these organisms grow in the laboratory. Consequently, this limited resource of culturable soil organisms has been overmined, leading to the subsequent drought of new antibiotics. Laboratory-based generation of synthetic antibiotics has been unsuccessful and has not been able to replace natural products.

To overcome this problem, Ling and colleagues focused on taking advantage of the 99% of microbial species in the external environment that are unculturable, by developing new methods for growing these bacteria. The authors designed an in situ miniaturized “iChip” diffusion chamber with multiple channels to isolate and grow unculturable bacteria in a diluted soil sample. After the bacteria and soil were added to the chip, the device was covered with semipermeable membranes and placed back in the soil. Additional nutrients and growth factors then diffused through the chamber to allow for growth of uncultured bacteria in their natural environment. Through such an approach, the researchers discovered an entirely new class of antibiotics named teixobactin in a new species of bacteria (Eleftheria terrae) found in a field in Maine, making this one of the first antibiotic classes discovered in decades. The authors used cultured mammalian cells and mouse infection models to show that teixobactin is effective against several drug-resistant strains of bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and Mycobacterium tuberculosis. They also found that teixobactin inhibits cell wall synthesis by binding to highly conserved lipids that are the precursors of bacterial cell wall teichoic acid and peptidoglycans. The mechanism of action of this antibiotic made it extremely difficult for microbes to develop a resistance to it, and none has been detected so far. Only time will tell whether the clinical use of teixobactin will result in substantial resistance.

This approach opens up new opportunities for drug discovery by tapping into compounds with low susceptibility to resistance that may be present in previously unculturable bacteria found in nature. This discovery is certainly a promising and timely answer to the current epidemic of antimicrobial resistance.

L. L. Ling et al., A new antibiotic kills pathogens without detectable resistance. Nature 517, 455–459 (2015). [Abstract]

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