Finally, an antibiotic that kills pathogens like MRSA without resistance

January 9, 2015

The iChip houses growing microorganisms, using semi-permeable membranes (shown as circles) on each side of the plate. After adding agar nutrient, it is placed in the soil from which the sample originated. (Credit: Losee L. Ling et al./Nature)

North­eastern University researchers have dis­cov­ered an antibi­otic called “teixobactin” that elim­i­nates pathogens without encoun­tering any detectable resistance — a finding that chal­lenges long-held sci­en­tific beliefs and holds great promise for treating chronic infec­tions like tuber­cu­losis and those caused by MRSA.

Pathogens’ resis­tance to antibi­otics is causing a public health crisis, according to Northwest’s Uni­ver­sity Dis­tin­guished Pro­fessor Kim Lewis.

Lewis’ lab played a key role in ana­lyzing and testing teixobactin for resis­tance from pathogens. Lewis said this marks the first dis­covery of an antibi­otic to which resis­tance by muta­tions of pathogens have not been identified.

The research was published Wednesday Jan. 7 in the journal Nature. Lewis and North­eastern biology pro­fessor Slava Epstein co-authored the paper with col­leagues from the Uni­ver­sity of Bonn in Ger­many, Novo­Bi­otic Phar­ma­ceu­ti­cals in Cam­bridge, Mass­a­chu­setts, and Selcia Lim­ited in the United Kingdom.

Finally a solution for MRSA

The research team says teixobactin’s dis­covery presents a promising new oppor­tu­nity to treat chronic infec­tions caused by staphy­lo­coccus aureus (MRSA), the “superbug” that infects 1 mil­lion Amer­i­cans annu­ally and which is highly resis­tant to antibi­otics; and tuber­cu­losis, which requires a com­bi­na­tion of ther­a­pies, with neg­a­tive side effects.

The screening of soil microor­gan­isms has pro­duced most antibi­otics, but only 1 per­cent of them will grow in the lab, and this lim­ited resource was over­mined in the 1960s, Lewis explained.

He and Epstein spent years seeking to address this problem by tap­ping into a new source of antibi­otics beyond those cre­ated by syn­thetic means: uncul­tured bac­teria, which can’t be grown in a petri dish and make up 99 per­cent of all species in external envi­ron­ments.

How to grow uncultured bacteria: resistance is futile

They devel­oped a novel method for growing uncul­tured bac­teria in their nat­ural envi­ron­ment, which led to the founding of Novo­Bi­otic. Their approach is based on the iChip, a minia­ture device Epstein’s team cre­ated that can iso­late and help grow single cells in their nat­ural envi­ron­ment, pro­viding researchers with much improved access to uncul­tured bac­teria. Novo­Bi­otic has so far assem­bled about 50,000 strains of uncul­tured bac­teria and dis­cov­ered 25 new antibi­otics, of which teixobactin is the latest and most inter­esting, Lewis said.

The antibi­otic was dis­cov­ered during a rou­tine screening for antimi­cro­bial mate­rial using this method. Lewis then tested the com­pound for resis­tance devel­op­ment and did not find mutant MRSA or Mycobac­terium tuber­cu­losis resis­tant to teixobactin, which was found to block sev­eral dif­ferent tar­gets in the cell wall syn­thesis pathway.

“Our impres­sion is that nature pro­duced a com­pound that evolved to be free of resis­tance,” Lewis said. “This chal­lenges the dogma that we’ve oper­ated under that bac­teria will always develop resis­tance. Well, maybe not in this case.”

Going for­ward, the research team hopes to develop teixobactin into a drug.

In 2013, Lewis revealed ground­breaking research in a sep­a­rate paper pub­lished by Nature that pre­sented a novel approach to treat and elim­i­nate MRSA: a way to destroy the dor­mant per­sister cells, which are key to the suc­cess of chronic infec­tions caused by MRSA.

Lewis said this latest research lays new ground to advance his inno­v­a­tive work on treating MRSA and other chronic infections.

Abstract of A new antibiotic kills pathogens without detectable resistance

Antibiotic resistance is spreading faster than the introduction of new compounds into clinical practice, causing a public health crisis. Most antibiotics were produced by screening soil microorganisms, but this limited resource of cultivable bacteria was overmined by the 1960s. Synthetic approaches to produce antibiotics have been unable to replace this platform. Uncultured bacteria make up approximately 99% of all species in external environments, and are an untapped source of new antibiotics. We developed several methods to grow uncultured organisms by cultivation in situ or by using specific growth factors. Here we report a new antibiotic that we term teixobactin, discovered in a screen of uncultured bacteria. Teixobactin inhibits cell wall synthesis by binding to a highly conserved motif of lipid II (precursor of peptidoglycan) and lipid III (precursor of cell wall teichoic acid). We did not obtain any mutants of Staphylococcus aureus or Mycobacterium tuberculosis resistant to teixobactin. The properties of this compound suggest a path towards developing antibiotics that are likely to avoid development of resistance.