Teixobactin: A Promising New Antibiotic Against Gram-Positive Infectious Bacteria

Although teixobactin is ineffective against most gram-negative organisms, its potent activity against gram-positive organisms, including vancomycin-resistant enterococci, may help delay the postantibiotic era by decades.

An antibiotic recently identified in soil microorganisms may lead to new treatments that are less susceptible to drug resistance than other antibiotics, according to researchers Ling and colleagues in a report published online in the journal Nature on January 7, 2015.

Although microorganism screening techniques in soil bacteria have been the source of many antibiotics in the past, these techniques were limited to bacteria in soil that could be grown on conventional media. By using novel culture techniques, investigators examined a broader spectrum of soil bacteria.

It is estimated that previous bacterial culturing techniques enabled investigation of just 1% of soil bacteria. Using specific growth factors and in situ bacteria cultivation techniques, investigators were able to grow more of the previously uncharacterized 99% of soil bacteria and the compounds produced by those organisms.

Results of these new screening techniques led to the development of a new 1242-Dalton, 11-amino acid antibiotic compound named teixobactin, which comes from a newly discovered gram-negative bacterial species with the provisional name Eleftheria terrae. Like other antibiotics, teixobactin inhibits cell wall synthesis by binding to precursors of 2 cell wall components: teichoic acid, and peptidoglycan.

Investigators unsuccessfully attempted to develop mutant strains of Staphylococcus aureus and Mycobacteria tuberculosis resistant to teixobactin. Even when the bacteria were exposed to a very low dose of the antibiotic below the minimum inhibitory concentration (MIC) over 27 days, no resistant mutant bacteria developed. However, use of low-dose teixobactin may not be necessary given that teixobactin did not exhibit toxicity against mammalian cells, even at the highest dose administered.

Like vancomycin, teixobactin inhibits formation of linkages between N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM) units that are the basis if peptidoglycans. Unlike vancomycin, however, teixobactin is able to bind to a modified form of lipid in the cell wall of vancomycin-resistant enterococci that grants these bacteria resistance against vancomycin.

Teixobactin also binds to teichoic acid in the cell wall, which contributes to the antibiotic's cell killing activity. Normally, teichoic acids help slow hydrolysis of peptidoglycans by binding to substances that trigger cell autolysis (self-killing). Teixobactin’s suppression of this anti-autolytic response contributes to its bactericidal potency.

In animal studies, mice maintained higher-than-MIC levels of teixobactin for 4 hours with a single 20 mg/kg dose. All mice treated with teixobactin survived infection with intraperitoneally introduced methicillin-resistant Staphylococcus aureus (MRSA)—an infection that normally has a 90% mortality rate in similar mice. Additionally, teixobactin has good lung penetration. In a mouse model, teixobactin also effectively reduced colony-forming units of Streptococcus pneumoniae by a factor of 1 million.

Although teixobactin successfully kills vancomycin-resistance enterococci, investigators note that resistance will probably appear eventually, but resistance may be decades away. For instance, 30 years passed before infectious bacteria evolved resistance to vancomycin.

Importantly, teixobactin is not a panacea against all bacteria. Because teixobactin inhibits bacterial cell wall synthesis, and because gram-negative bacterial cell walls are more protected than those of gram-positive bacteria, teixobactin is ineffective against the majority of gram-negative bacteria. Despite this limitation, the discovery of teixobactin is welcome news in an era of ever-more-common drug-resistant superinfections and rising rates of antibiotic resistance.

Reference

Ling LL, Schneider T, Peoples AJ, et al. A new antibiotic kills pathogens without detectable resistance [published online January 7, 2015]. Nature.