Journal Article

A new antibiotic kills pathogens without detectable resistance

Cohen, Douglas R., Zullo, Ashley M., Epstein, Slava, Steadman, Victoria A., Fetterman, K. Ashley, Millett, William P., Jones, Michael, Spoering, Amy L., Hughes, Dallas E., Schneider, Tanja, Conlon, Brian P., Lewis, Kim, Schäberle, Till F., Lazarides, Linos, Felix, Cintia R., Engels, Ina, Chen, Chao, Peoples, Aaron J., Nitti, Anthony G., Mueller, Anna, Ling, Losee L.

2015

Overview

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. From a new species of β-proteobacteria, an antibiotic called teixobactin that does not generate resistance has been characterized; the antibiotic has two different lipid targets in different bacterial cell wall synthesis components, which may explain why resistance was not observed. Teixobactin, a robust dual-action antibiotic Most antibiotics in clinical use were discovered by screening cultivable soil microorganisms, a much depleted resource that has not been adequately replaced by synthetic approaches. Hence the widespread alarm at the spread of antibiotic resistance. This paper presents some welcome good news, in the form of the isolation and characterization of a new antibiotic active against a range of bacterial pathogens including Staphylococcus aureus , and apparently untroubled by the evolution of resistance. Kim Lewis and colleagues use a recently developed system for in situ cultivation of previously uncultured soil bacteria and identify a β-proteobacterium, Eleftheria terrae sp. that produces a depsipeptide they call teixobactin. Teixobactin is active in vivo and separately targets precursors in the biosynthetic pathways for each of two major components of the bacterial cell wall, peptidoglycan and teichoic acid. Screens for mutants resistant teixobactin were negative, perhaps a consequence of this novel two-target mechanism.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/154/349 / 631/154/555 / 631/326/22/1290 / 631/326/22/1434 / Analysis / Animals / Anti-Bacterial Agents - biosynthesis / Anti-Bacterial Agents - chemistry / Anti-Bacterial Agents - isolation & purification / Anti-Bacterial Agents - pharmacology / Antibiotic resistance / Antibiotics / Antimicrobial agents / Bacteria / Bacteriology / Betaproteobacteria - chemistry / Betaproteobacteria - genetics / Biological Products - chemistry / Biological Products - isolation & purification / Biological Products - pharmacology / Biosynthesis / Cell Wall - chemistry / Cell Wall - drug effects / Cell Wall - metabolism / Deoxyribonucleic acid / Depsipeptides - biosynthesis / Depsipeptides - chemistry / Depsipeptides - isolation & purification / Depsipeptides - pharmacology / Disease Models, Animal / DNA / Drug dosages / Drug resistance / Drug resistance in microorganisms / Drug Resistance, Microbial - genetics / Enzymes / Female / Growth factors / Health aspects / Humanities and Social Sciences / Lipids / Mice / Microbial Sensitivity Tests / Microbial Viability - drug effects / Microorganisms / Molecular Sequence Data / multidisciplinary / Multigene Family - genetics / Mycobacterium tuberculosis - cytology / Mycobacterium tuberculosis - drug effects / Mycobacterium tuberculosis - genetics / Peptidoglycan - biosynthesis / Proteins / Public health / Science / Soil microbiology / Soil microorganisms / Staphylococcal Infections - drug therapy / Staphylococcal Infections - microbiology / Staphylococcus aureus - chemistry / Staphylococcus aureus - cytology / Staphylococcus aureus - drug effects / Staphylococcus aureus - genetics / Teichoic Acids - biosynthesis / Time Factors