Teixobactin appears to avoid bacteria resistance [PreClinical]

1. The newly discovered antibacterial compound teixobactin, isolated from the soil bacteria Eleftheria terrae, targeted cell wall synthesis in gram-positive bacteria without leading to resistant mutants.

2. In three mouse models of bacterial infection, teixobactin showed comparable efficacy to current antibiotics.

Evidence Rating Level: 2 (Good)

Study Rundown: The dual problem of antibiotic resistance and development limitations has become a global health issue. This study addressed both aspects of the problem by developing a novel method for growing uncultured bacteria and identifying an antibiotic that appears to avoid bacterial resistance. First, the researchers employed the iChip device to culture soil bacteria as potential sources of naturally occurring antibiotic compounds. Such bacteria do not survive in standard in vitro bacteria culture environments. Second, teixobactin was isolated from the gram-negative species Eleftheria terrae and did not lead to resistance in treated bacteria.

Teixobactin was found to inhibit the growth of many gram-positive bacteria species, including M. tuberculosis and Clostridium difficile, though not gram-negative species. The compound targeted the synthesis of peptidoglycan, a main component of bacterial cell walls. In one typical mechanism of developing resistance to antibiotics, genetic mutations alter enzymes that are affected by the drug. However, this process did not impede teixobactin efficacy because the antibiotic acted on lipid molecules that are precursors of peptidoglycan. In three different mouse models of bacterial infection, treatment with teixobactin improved outcomes at levels comparable to antibiotics currently on the market.

In addition to characterizing a new antibiotic with advantageous properties, this study supports a return to the natural product discovery approach to drug development—i.e. screening naturally occurring compounds for activities of interest. While teixobactin was delivered intravenously in the animal experiments, future studies to develop other formulations of the drug could improve accessibility and ease of use. Overall, the study represents an exciting contribution to the fields of antibiotic use and development.

Click to read the study in Nature

Click to read an accompanying editorial in Nature

Relevant Reading: Use of Ichip for High-Throughput In Situ Cultivation of “Uncultivable” Microbial Species

In-Depth [in vitro and animal study]: The iChip device was used to culture soil bacteria species in a high-throughput manner. Because many species of soil bacteria cannot grow in standard laboratory media and conditions, the iChip comprised semi-permeable membranes that allowed bacteria access to their natural soil environment. Teixobactin was identified by screening culture extracts for antimicrobial activity.

In vitro tests showed that teixobactin was effective in inhibiting the growth of many gram-positive bacteria species, including a number of drug-resistant strains. Minimum inhibitory concentrations were low for Staphylococcus (S.) aureus (0.25μg/mL), Clostridium difficile (0.005μg/mL), and Mycobacterium tuberculosis (0.125μg/mL). In contrast, teixobactin was not effective against gram-negative bacteria including Pseudomonas aeruginosa and Klebsiella pneumoniae, with minimum inhibitory concentrations of over 32μg/mL. Culturing S. aureus in the presence of low levels of teixobactin over the course of 27 days did not lead to resistance acquisition by the bacteria. Teixobactin did not kill mammalian cells. By using labeled precursors of RNA, DNA, protein, and peptidoglycan to study biosynthesis of the macromolecules, teixobactin was shown to inhibit peptidoglycan synthesis. Teixobactin acted by binding to the peptidoglycan precursors lipid II and lipid III.

In a mouse model of methicillin-resistant S. aureus (MRSA) septicemia, the protective dose at which half the animals survived was 0.2mg/kg for teixobactin compared to 2.75mg/kg for vancomycin. In a mouse thigh model of MRSA infection, the decrease in bacteria levels at 26 hours post-infection was similar between treatment with teixobactin and vancomycin. In a mouse lung model of Streptococcus pneumoniae infection, decrease in bacteria levels at 48 hours post-infection was similar between treatment with teixobactin and amoxicillin.

More from this author: Novel system rapidly detects low levels of bacteria in blood, Cell-loaded scaffold implant may improve cell therapy, Vaccines for predicted influenza strains may provide wide protection, Key gut bacteria may prevent Clostridium difficile infection

Image: PD/CDC

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