Ichip and teixobactin

Nature 517,455–459 (22 January 2015)

K.Lewis.Nature Rev Drug Disc 12: 371-387(2013)

Introduction

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Resistance development limits the useful lifespan of antibiotics and results in the requirement for a constant introduction of new compounds.

Most antibiotics introduced into the clinic were discovered by screening cultivable soil microorganisms and overmining of this limited resource by the 1960s brought an end to the initial era of antibiotic discovery.

Antimicrobial drug discovery and synthetic approach is uniquely difficult, primarily due to poor penetration of compounds into bacterial cells.

Approximately 99% of all species in external environments are uncultured (do not grow under laboratory conditions), and are a promising source of new antibiotics.

Used method to grow uncultured organisms by cultivation in their natural environment and discovered a low resistance antibiotic Teixobactin.

K.Lewis.Nature 485: 439-440(2012)

Reviving the Waksman platform

Winterberg H. (1898) Zur Methodik der Bakterienzahlung. Zeitschr f Hyg 29: 75-93

Uncultured Bacteria

Diffusion chamber

Nicholas et.al.,2008

Nichols et al.,2010. Appl.Environ.Microbiol.76: 2445-2450

How isolation chip/ichip works?

Extracts from 10,000 isolates obtainedby growth in iChips

Discovery of 25 promising candidates

including the most promising-

TEIXOBACTIN from a new species Eleftheria

terrae

How teixobactin discovered?

A low resistance antibiotic

The MIC was determined by broth microdilution. MSSA, methicillin-sensitive S. aureus; VRE, vancomycin-resistant enterococci.

Teixobactin spectrum

Killing of S.aureus by teixobactin

Teixobactin has excellent bactericidal activity against S. aureus and superior to vancomycin in killing late exponential phase populations

Teixobactin resistance development

Specificity of action

Finding the targets

Teixobactin: mechanism of action

Efficacy of teixobactin in mouse models

Septicemia protection(MRSA) Mouse thigh(MRSA) Mouse lung, S.pneumoniae

Limitations

No activity against Gram-negative bacteria. Since the source Elftheria terrae, is a Gram-negative bacterium, this is no surprise, otherwise it would inhibit itself in the soil.

Only tested in mice, the antibiotic is still a long way from the clinic, and has to undergo a series of rigorous human clinical trials before reaching the pharmacy shelves.

There are several drugs which treats S.aureus and Enterococci, it would be more exciting to test teixobactin against more resistant strains of bacteria including VRSA,DRE,MDR/XDR TB.

Ofloxacin was used as control during resistance testing but Vancomycin would be better comparison as it also inhibit cell wall synthesis.

Although resistance to teixobactin was difficult to manufacture in lab, resistance could eventually emerge in the same manner vancomycin resistance emerged, through horizontal gene transfer.

Conclusions

A low resistance antibiotic teixobactin isolated with a new tool, the iChip, that allowed the environmental bacterium to grow in their natural environment.

This antibiotic has activity against Gram-positive (but not Gram-negative) organisms and a novel mode of action inhibiting peptidoglycan biosynthesis.

In vitro no teixobactin-resistant Staphylococcus aureus or Mycobacterium tuberculosis were obtained.

In experimental infections of MRSA and Streptococcus pneumoniae in mice, teixobactin was effective at reducing the bacterial load.

Teixobactin is a promising therapeutic candidate; it is effective against drug-resistant pathogens in a number of animal models of infection.

Future perspectives Uncultured bacteria are promising platform for reviving antibiotics discovery. The use of the

iChip will hopefully result in the discovery of further potential new antibiotics.

However, as teixobactin is active against M. tuberculosis, it could offer the opportunity for a new treatment for patients with TB.

For teixobactin 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.

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.