This document discusses recent advances to overcome antibiotic resistance. It begins with an introduction to antibiotic resistance and defines some superbugs. It then discusses the history of antibiotics from Ehrlich discovering chemotherapy to current generations. Common causes and modes of resistance are described. New classes of antibiotics are discussed like oxazolidinones, glycopeptides, ketolides, glycylcyclines, carbapenems, and cephalosporins. New targets for next generation drugs and possible solutions to antibiotic resistance are also presented.

1. Recent Advances to overcome
Antibiotic Resistance
Dr.Akhilesh
M-5698
M.V.Sc Scholar
VETERINARY MEDICINE

2. Contents
 Introduction
 History
 Common causes
 Common modes of AR
 Most resistant pathogens
 Newer antibacterials
 New Targets for the Next Generation of Antimicrobial drugs
 Possible Solutions for Antibiotic Resistance

3. Introduction
 Antimicrobial resistance (AMR) is the ability of a
microorganism to stop an antimicrobial from working against
it. As a result, standard treatments become ineffective,
infections persist and may spread to others.
 Antibiotic / Antimicrobial resistance is the ability of microbes
to resist the effects of drugs.
 The ability of pathogens that works against the antibiotics, is
termed Antibiotic Resistance.
[1]
(1. www.who.int/drugresistance/en/)

4. Superbug
 An informal term for a bacterium that has become resistant
to antibiotics that usually are used to treat it.
Ex:Methicillin-resistant Staphylococcus aureus (MRSA)
Vancomycin-resistant Enterococcus (VRE)
(Rakel RE and Rakel D,2015 )
(Fri, Sep 16,2016)

5. History
PAUL EHRLICH
 Coined the term “CHEMOTHERAPY”
 Discovered Salvarsan (for Syphilis)
 FATHER OF CHEMOTHERAPY
 He used the term ‘MAGIC BULLETS’
(Stefan H. E. Kaufmann,2008)

6. …..history
ALEXANDER FLEMING
 Penicillin
 Discovered in London
in Sep,1928
 Accidental discovery
while working on
S.aureus

7. …..history
 Domagk discovered “Sulphonamides”
 Selman Waksman discovered
“Streptomycin”
 In 1947, “chloramphenicol” was first used
clinically to treat Typhus
 G.Brotzu discovered “Cephalosporins”
 Benjamin M. Duggar isolated
“Chlortetracycline” from a mud sample
obtained from a river in Missouri.

8. …..history
 1960 onwards second generation
antibiotics like “Methicillin” were
discovered
 Following this, semi synthetic derivatives
of older antibiotics with more desirable
properties & different spectrum of activity
were produced
e.g. Fluroquinolones, Oxazolidinones etc.

9. Antimicrobial Targets

12. Evolution of Antibiotic Resistance

14. Common modes of antibiotic resistance

16. Why do we need newer antimicrobials
 Bacterial resistance to antimicrobials-
health and economic problem
 Chronic resistant infections contribute to
increasing health care cost
 Increase morbidity & mortality
with resistant microorganisms
[D.M. Livermore ,Clinical Microbiology & Infection
Volume 10, Supplement 4, Pages 1-36 (2004)]

18. Oxazolidinones
Considered to be the first truly new
class of antibacterial drugs introduced in
the past 3 decades
 Linezolid
 Approved for adults use in 2000
 Approved for pediatric
use in 2005

19. (Prasad Vara JV, 2007)

20. Mechanism of Resistance to
older Oxazolidinones
 Occurs due to mutations in ribosomal RNA
(rRNA)
 Resistance overcome by:
Newer oxazolidinones by additional
hydrogen bond interactions with 23S rRNA
(Jaswant Rai et al, 2013)

21. Newer glycopeptides
 Vancomycin & Teicoplanin are already in
use
 Recently APPROVED DRUG
 Telavancin :Approved in 2009 for complicated
skin and skin structure infections(MRSA)
 DRUGS IN PIPELINE
 Oritavancin : Phase III trial
 Dalbavancin : Phase III trial

22. Mechanism of resistance to older
glycopeptides.
 Synthesis of low-affinity precursors in
which C-terminal D-Ala residue is replaced
by:
 D-lactate (D-Lac) or by D-serine (D-Ser)
 Resistance overcome by:
 High binding affinity for both substrates
(D-Ala-D-Lac precursor substrate OR D-
Ala-D-Ser) due to presence of
hydrophobic side chain. (Mandeep Kaur et al,2014)

23. Ketolides
 Drug resistance in community acquired
respiratory tract infections discovery
and development of ketolides.
 Carbonyl group at the C3 position, responsible for
sensitivity to macrolide resistant strains.

24. Newer ketolides
 APPROVED DRUG
 Telithromycin –Approved in 2004
 DRUGS IN PIPELINE
 Cethromycin- Phase III trails
 Solithromycin – Phase III trails

25. Mechanism of action

26. Glycylcyclines
 New class of antibiotic derived from
tetracycline
 Designed to overcome two common mechanisms
of tetracycline resistance
 Resistance mediated by acquired efflux pumps
 Ribosomal protection
 Only one glycylcycline antibiotic for
clinical use : TIGECYCLINE
(Frampton JE & Curran MP, Tigecycline Drugs,2005)

27. Newer Carbapenems
 Beta-lactum antibiotics with a broad
spectrum of antibacterial activity
 NEWER CARBAPENEMS :
 Ertapenem : Approved in 2001
 Doripenem : Approved in 2007
 DRUG IN PIPELINE :
 Razupenem : Phase II clinical trail
(Livermore DM, Mushtaq S, Warner M, 2009)

28. Newer Cephalosporins
 Approved Cephalosporins
 Ceftaroline: Approved in 2010
 For the treatment of
o Community – acquired pneumonia
o Complicated skin and soft – tissue
infections
 Drugs in pipeline
 Ceftobiprole : awaiting FDA approval
(Saravolatz LD et al, 2011)

29. New Targets for the Next
Generation of Antimicrobial drugs
 Targeting virulence factors
 Targeting bactericidal functions of
bacterial proteins
 Modulating host response pathways
 Peptides derived from vertebrates,
invertebrates and microorganism.
(Gurpreet Kaur Randhawa et al, 2013)

36. Possible Solutions for Antibiotic
Resistance
 Stop unnecessary antibiotic prescriptions.
 Finish antibiotic prescriptions.
 Use the right antibiotic in an infectious situation
as determined by antibiotic sensitivity testing.
 Use antibiotics in rotation.
 Use combination of antibiotics if necessary.
 Promote Vaccine recommendations.
 Implement infection control measures, such
as hand washing, isolation precautions, and
immunization.
 Improve communication, education and training.

37. Conclusion
 There is a great need of newer antibiotics
because of increasing microbial resistance
 Because of increase cost of development
and increasing resistant, only few drugs
are in pipeline
 Some of the newer agents are effective
against resistant strains
 Programs like Antibiotic stewardship can
be helpful to combat the resistance
 Rational use of antibiotics remains the
most important measure.

38. References
 www.who.int/drugresistance/en/
 www.cdc.gov › Antibiotic / Antimicrobial Resistance › U.S.
Activities to Combat AR
 http://www.sciencedaily.com/articles/a/antibiotic_resistanc
e.html
 Andrea Gyyot, Graham Layer,2006 MRSA Bugbear of a surgical
practice reducing the incidence of MRSA surgical site infection,
Ann R Coll Surg Engl: 88: 222-223.
 Archibald L(1997).Antimicrobial resistance in isolates from
inpatients and outpatients in the United States: increasing
importance of the intensive care unit. Clinical Infectious Diseases.
24(2):211-215
 Ceasr A, Arias, M.D. and Balbara E. Murray, M.D.N., 2009.
Antibiotic resistant Bugs in the 21st Century. A clinical super
challenge. Eng. J. Med.: 360: 439-443

39.  Microbiology, A clinical Approach -Danielle Moszyk-Strelkauskas-
Garland Science 2010
 Jaswant Rai, Gurpreet Kaur Randhawa, and Mandeep Kaur,
Recent advances in antibacterial drugs, Int J Appl Basic Med
Res. 2013 Jan-Jun; 3(1): 3–10.
 D.M. Livermore ,Clinical Microbiology & Infection Volume
10, Supplement 4, Pages 1-36 (2004)
 Vikas Manchanda, Sinha Sanchaita, and NP Singh J. Glob
Infect Dis. 2010 Sep-Dec; 2(3): 291–304.
 Losee L. Ling et al, A new antibiotic kills pathogens without
detectable resistance, Journal Nature 517, 455–459 (22 January
2015)