As you may have seen in the news earlier this year, there is a new potential antibiotic in testing with activity against gram-positives (and even AFB such as M TB) and, as some have noted, no potential for antibiotic resistance (yet). This antibiotic, Teixobactin, was discovered using a novel technique, referred to as the I-Chip. Teixobactin is the first member of a novel class of peptidoglycan synthesis inhibitors (Ling et al., 2015). The compound is highly potent against a broad range of Gram-positive microbes, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). Teixobactin binds to two different targets – lipid II (peptidoglycan precursor) and lipid III (teichoic acid precursor). It binds to the undecaprenyl-PP-sugar region of these precursors, which is not known to be modified. As a result, teixobactin is the first example of a target-specific compound essentially free of resistance. Teixobactin shows excellent activity in several models of infection, and is in preclinical development.
Teixobactin had excellent activity against Gram-positive pathogens, including drug-resistant strains. Potency against most species, including difficult-to-treat enterococci and M. tuberculosis was below 1 µg ml−1. Teixobactin was exceptionally active against Clostridium difficile and Bacillus anthracis (minimal inhibitory concentration (MIC) of 5 and 20 ng ml−1, respectively). Teixobactin had excellent bactericidal activity against S. aureus, was superior to vancomycin in killing late exponential phase populations, and retained bactericidal activity against intermediate resistance S. aureus (VISA). Note that frequent clinical failure in patients with S. aureus MRSA treated with vancomycin has been linked to the poor bactericidal activity of this compound. Teixobactin was ineffective against most Gram-negative bacteria, but showed good activity against a strain ofE. coli asmB1 with a defective outer membrane permeability barrier.
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- Nature 517, 455–459, (22 January 2015). doi:10.1038/nature14098
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.
A multichannel device, the iChip, was used to simultaneously isolate and grow uncultured bacteria. A sample of soil is diluted so that approximately one bacterial cell is delivered to a given channel, after which the device is covered with two semi-permeable membranes and placed back in the soil. Diffusion of nutrients and growth factors through the chambers enables growth of uncultured bacteria in their natural environment. The growth recovery by this method approaches 50%, as compared to 1% of cells from soil that will grow on a nutrient Petri dish. Once a colony is produced, a substantial number of uncultured isolates are able to grow in vitro. Extracts from 10,000 isolates obtained by growth in iChips were screened for antimicrobial activity on plates overlaid with S. aureus. An extract from a new species of β-proteobacteria provisionally named Eleftheria terrae showed good activity. The genome of E. terrae was sequenced. Based on 16S rDNA and in silico DNA/DNA hybridization, this organism belongs to a new genus related to Aquabacteria. This group of Gram-negative organisms is not known to produce antibiotics. A partially purified active fraction contained a compound with a molecular mass of 1,242 Da determined by mass spectrometry, which was not reported in available databases. The compound was isolated and a complete stereochemical assignment has been made based on NMR and advanced Marfey’s analysis. This molecule, which we named teixobactin, is an unusual depsipeptide which contains enduracididine, methylphenylalanine, and four D-amino acids. The biosynthetic gene cluster (GenBank accession number KP006601) was identified using a homology search. It consists of two large non-ribosomal peptide synthetase (NRPS)-coding genes, which we named txo1 and txo2, respectively. In accordance with the co-linearity rule, 11 modules are encoded. The in silico predicted adenylation domain specificity perfectly matches the amino acid order of teixobactin, and allowed us to predict the biosynthetic pathway.
For more information about this technology, read the original article on Nature.
Nature 517, 455–459 (22 January 2015). doi:10.1038/nature14098