A new antibiotics kills pathogens without detectable resistance

2. Nature 517,455–459 (22 January 2015)

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

4. www.scq.ubc.ca

5. 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.

6. K.Lewis.Nature 485: 439-440(2012)
Reviving the Waksman platform

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

8. Diffusion chamber
Nicholas et.al.,2008

9. Nichols et al.,2010. Appl.Environ.Microbiol.76: 2445-2450
How isolation chip/ichip works?

12. Extracts from 10,000
isolates obtained
by growth in iChips
Discovery of 25
promising candidates
including the most
promising-
TEIXOBACTIN from a
new species Eleftheria
terrae
How teixobactin discovered?

13. A low resistance antibiotic

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

15. Killing of S.aureus by teixobactin
Teixobactin has excellent bactericidal activity against S. aureus and
superior to vancomycin in killing late exponential phase populations

16. Teixobactin resistance development

17. Specificity of action

18. Finding the targets

19. Teixobactin: mechanism of action

20. Efficacy of teixobactin in mouse models
Septicemia protection(MRSA) Mouse thigh(MRSA) Mouse lung, S.pneumoniae

21. 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.

22. 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.

23. 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.