A new antibiotic kills pathogens without detectable resistance

Abstract

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.

Targeting Antibiotic Resistance

“…Structural and mechanistic understanding of antibacterial targets and deciphering of the bacterial ability for developing antibiotic resistance provide a sound basis for rational campaigns against antibiotic resistance. Screening for new natural or synthetic compounds with antibiotic effects based on novel antibacterial targets still provide one route to outstanding discoveries in the field203 but structural knowledge enables us to work directly on the resistance mechanisms with increasing success, as shown by some selected examples in this review. A multipronged strategy that involves targeting traditional and emerging antibiotic targets as well as pursuing adjuvant strategies at the genetic level with non‐antibiotic compounds for potentiating known antibiotics gives rise to many opportunities to overcome antibiotic resistance.…”

Antibiotic drug discovery

“…This screening approach already led to the discovery of several new effective natural compounds, such as the protein synthesis inhibitor orthoformimycin, which is a structurally novel substance that follows a completely new mechanism of action or the class III lanthipeptide NAI‐112, which is a potent anti‐inflammatory agent (Monciardini et al ., 2014). Another recent successful example for the identification of a novel anti‐infective substance from a previously uncultured bacterium is represented by teixobactin, which is a substance from the novel species of β‐proteobacteria named Eleftheria terrae (Ling et al ., 2015). E. terrae was isolated with the help of a new cultivation technique, the so‐called iChip, which is a multichannel device composed of several hundred miniature diffusion chambers, each inoculated with a single environmental cell.…”

Dual Targeting of Cell Wall Precursors by Teixobactin Leads to Cell Lysis

“…One such organism, Eleftheria terrae, a previously uncultivated Gram-negative betaproteobacterium, was found to produce a novel depsipeptide antibiotic, called teixobactin. Teixobactin inhibits cell wall biosynthesis and represents a new class of antibiotics (5).…”