Teixobactin, the first of a new class of antibiotics discovered by iChip technology?
Teixobactin is a recently described antibiotic of a new class produced by a hitherto undescribed soil microorganism (provisionally named Eleftheria terrae). It was isolated with a new tool, the iChip, that allowed the environmental bacterium to grow and for the antibiotic,, it produced to be isolated and subsequently identified. Teixobactin has activity against Gram-positive (but not Gram-negative) organisms and mycobacteria and a novel mode of action inhibiting peptidoglycan biosynthesis. In vitro,, no teixobactin-resistant Staphylococcus aureus or Mycobacterium tuberculosis were selected. In experimental infections of MRSA and Streptococcus pneumonia in mice, teixobactin was effective at reducing the bacterial load. Although teixobactin is at an early stage of development and there are no guarantees it will make it to market, the use of the iChip will hopefully result in the discovery of further potential new antibiotics.
Teixobactin: spectrum of activity, mode of action and development of resistance
This new antibiotic is produced by a new species of b-proteobacteria provisionally named Eleftheria terrae, which belongs to a new genus related to Aquabacteria. The authors showed that teixobactin was able to kill representative strains of bacteria that cause wound and invasive infections such as S. aureus including MRSA, those that cause pneumonia (Streptococcus pneumonia) and Mycobacterium tuberculosis. It also showed good activity against Clostridium difficile and Bacillus anthracis. Teixobactin was also effective as a single dose in significantly reducing bacterial numbers in mouse models of MRSA septicaemia and pneumococcal pneumonia.
From the culture supernatant of E. terrae,, a partially purified active fraction was obtained and shown to contain a compound, teixobactin. It is an unusual depsipeptide containing enduracididine, methylphenylalanine and four D-amino acids. The biosynthetic pathway of teixobactin was identified by genome sequencing of E. terrae and homology searches.
Teixobactin has a different mode of action from other antibiotics currently used to treat bacterial infections in people (and animals). Ling et al. 1 showed that teixobactin inhibits peptidoglycan biosynthesis in S. aureus by binding to a highly conserved motif of lipid II (a precursor of peptidoglycan) and lipid III (a precursor of teichoic acid). No teixobactin-resistant S. aureus or M. tuberculosis was isolated at four times the MIC. Furthermore, no resistant
S. aureus was obtained after serial passage in subinhibitory concentrations of teixobactin. This led the authors to suggest that it will be difficult for bacteria that cause infections in people to become resistant to teixobactin. However, teixobactin is a natural product from a microorganism that lives in the soil. Many antibiotics have been discovered from the natural environment, and the microorganism that produces the antibiotic, and sometimes its close microbial neighbours, are resistant to the antibiotic.4–6 For the producing microorganism, resistance is essential, otherwise,, production of its own antibiotic would cause the microorganism to kill itself. Likewise, close neighbour environmental microorganisms can be resistant so that they can survive in the same environment as the producing microorganism. ‘Natural’ antibiotic resistance genes can be transferred into pathogenic bacteria.7 Indeed, the gene encoding one of the most common mechanisms of antibiotic resistance, ESBLs, was acquired from an environmental bacterium.8 This is the most likely route of any resistance, should it occur, to teixobactin. However, this could be a very rare occurrence because the bacterial strains that cause infection in people would need to have mixed with the teixobactin-resistant soil bacteria. Nonetheless, to be sure that resistance to teixobactin is unlikely to occur when used in human medicine, bacteria isolated from the same environmental niche as the teixobactin producing organism should be screened for teixobactin-resistance conferring genes.
Activity against Gram-negative bacteria
According to the WHO’s report on April 2014,9, one of the major global concerns of physicians is antibiotic resistance in Gramnegative bacteria such as Escherichia coli and Klebsiella spp. The Gram-negative bacterial cell envelope structure makes it difficult for many antibiotics to gain entry into the bacterium and once inside many antibiotics are exported by multidrug efflux pumps.10 Ling et al. 1 showed that teixobactin had no activity against E. coli, suggesting that E. coli is impermeable to this agent or it is effluxed (or both). Either way, teixobactin does not inhibit E. coli and so is unlikely to be effective against other Gram-negative bacteria.
Will teixobactin be developed into a new drug? For teixobactin (and any new compound with antimicrobial activity) to become a drug to treat infections in people, clinical trials will need to be carried out to make sure that the drug is safe, well-tolerated and efficacious in patients. To do this, teixobactin will need to be formulated so that the antibiotic remains active in vivo at clinically relevant sites of infection. Full toxicology tests will also need to be carried out to ensure that there are no adverse reactions or drug-drug interactions following administration of teixobactin. NovoBiotic Pharmaceuticals owns the novel chemical entities produced by the ship and it has been stated that the hope is that teixobactin will be ready for a clinical trial in 2017. Whether it will be fully developed as a new drug remains to be seen, not least because it is questionable whether more drugs against Gram-positive bacteria are required. However, as teixobactin is active against M. tuberculosis, it could offer the opportunity for a new treatment for patients with TB. Teixobactin may also fulfil the requirements for approval by the FDA under the qualified infectious disease product (QIDP) framework, as envisaged in the USA Generating Antibiotic Incentives Now (GAIN) Act, so it could be licensed quickly. Even if teixobactin itself cannot be turned into a new drug, it is probably the first of a series of new antibiotics in its class.
Author: Laura J. V. Piddock*