Bacterial Antibiotic Resistance Old genes, new problems by Anila Sajjad

1. Bacterial Antibiotic Resistance
Old genes, new problems
Presented By: Anila Sajjad

2. Throughout history there has been a continual battle
between human beings and multitude of micro-
organisms that cause infection and disease.

3. Microbial Pathogenesis
Entry into the Host
Must access and adhere to host tissues, penetrate or evade
host defenses, and damage tissue to cause disease.
Portals of Entry
The three main portals of entry are:
• Mucous membranes
• Skin
• Parenteral

4. Mechanisms of Bacterial Resistance :
how DO they do it ??

5. • Resistant organisms lead to treatment
failure
• Increased mortality
• Resistant bacteria may spread in
Community
• Low level resistance can go undetected
• Added burden on healthcare costs
• Threatens to return to pre-antibiotic era
• Selection pressure
Why is a concern resistance?

6. Antibiotic Resistance
• Defined as micro-organisms that are not inhibited by
usually achievable systemic concentration of an
antimicrobial agent with normal dosage schedule and
/ or fall in the minimum inhibitory concentration
(MIC) range.
• The concentration of drug at the site of infection
must inhibit the organism and also remain below the
level that is toxic to human cells.
Silver L. L, 2011

7. Antibiotic Resistant Bacteria Are:
• Bacteria that mutate and are able to resist the
antibiotics that are meant to kill them.
• This is a normal process speeded up by the overuse
and misuse of antibiotics. Bacteria that mutate and are
able to resist the antibiotics that are meant to kill
them.
• Antibiotic that are meant to kill them.
• This is a normal process speeded up by the overuse
and misuse of antibiotics.
Silver L. L, 2011

9. Cassir, N; (2014)

10. Bacteria: Mechanism of Resistance
Levy et al. 2004

11. There are four major mechanisms that
mediate bacterial resistance to drugs
(1)Bacteria produce enzymes that inactivate the drug;
eg, lactamases can inactivate penicillins and
cephalosporins by cleaving the lactam ring of the drug.
(2) Bacteria synthesize modified targets against which the
drug has no effect; eg, a mutant protein in the 30S
ribosomal subunit can result in resistance to streptomycin,
and a methylated 23S rRNA can result in resistance to
erythromycin.

13. Silver L. L, 2011

14. (3) Bacteria decrease their permeability such that an
effective intracellular concentration of the drug is not
achieved; eg., changes in porins [membrane transport
proteins] can reduce the amount of penicillin entering the
bacterium.
(4) Bacteria actively export drugs using a "multidrug
resistance pump" (MDR pump, or "efflux" pump).
The MDR pump imports protons and, in an exchange-type
reaction, exports a variety of foreign molecules including
certain antibiotics, such as quinolones.
•
Alekshun M N, 2007

15. Efflux mediated antibiotic resistance in
Gram-negative bacteria
Li X-Z, 2015

17. Wright G.D 2011

18. Alekshun M N, 2007

20. Cassir, N., 2014

21. Podschun R ,1998

22. Pseudomonas aeruginosa
•Pseudomonas aeruginosa is a Gram-negative rod shaped
bacteria. It is common inhabitant of soil, water and
vegetation.
•It is opportunistic pathogen: the disease process begins
with some alteration or circumvention of normal host
defense
•Nearly 70% of people with Cystic Fibrosis are
chronically infected with Pseudomonas aeruginosa.
•It causes a wide range of diseases, which include
septicemia, urinary tract infection, pneumonia, chronic
lung infections, endocarditic, and osteochondritis

23. Resistance Mechanism In Pseudomonas
aeruginosa
Li X-Z , 2015

25. Antibiotic resistance and MSRA
• Some strains of Staphylococcus aureus evolved because
resistant to one or more of the commonly used antibiotic
including methicillin. These are termed methicillin-
resistant staphylococcus aureus (MRSA)
• MSRA is especially prevalent in hospitals:
--Here patients tend to be more vulnerable to the infection
i.e. older, sicker and weaker
--People live together and are examined by doctors and
nurses that have touched other patients.
--Many antibiotic strains are used, any resistant strains
therefore have an advantage. Lowy FD, 2003

26. Lowy FD, 2003

27. Silver, L. L. , 2011

28. Alekshun M N, 2007

29. Alekshun M N, 2007

30. Modification/Protection of the Target site
Resistance resulting from altered target sites :
Target sites Resistant Antibiotics
Ribosomal point mutation Tetracyclines, Macrolides,
Clindamycin
Altered DNA gyrase Fluoroquinolones
Modified penicillin binding
proteins (Strepto.pneumonia)
Penicillines
Mutation in DNA dependent
RNA polymerase
(M. tuberculosis)
Rifampicin
Wright G.D 2011

31. SELECTION OF RESISTANT BACTERIA BY
OVERUSE & MISUSE OF ANTIBIOTICS
• Prescribe unnecessarily long courses of antibiotic therapy
• Sold over the counter to the general public
• Antibiotics are used in animal feed to prevent infections
and promote growth

32. References:
1. AlekshunMN, et al., (2007) Molecular mechanisms of antimicrobial multi drug
resistance , cell, 128(6), 1037-50
2. Cassir, N; Rolain, JM; Brouqui, P (2014). “A new strategy to fight
antimicrobial resistance: the revival of old antibiotic”. Frontiers in Microbiology.
5: 55
3. Kruse, et al., (1994) Transfer of multi drug resistant plasmids between bacteria
of diverse origins in natural microenvironments, Applied and Environmental
Microbiology, p. 4015-4021
4. Li X-Z, Plésiat P, Nikaido H. 18 March 2015. The challenge of effluxmediated
antibiotic resistance in Gram-negative bacteria. Clin Microbiol Rev
doi:10.1128/CMR.00117-14
5. Lowy FD (2003), Antimicrobial resistance: the example of Staphylococcus
aureus, J clin invest, 111(9) : 1265-1273
6. Podschun R, et al., klebsiella spp. as nosocomial pathogen, clin microbiology
rev, 11(4) :589-603
7. Silver, L. L. (2011). Challenges of Antibacterial Discovery. Clinical
Microbiology Reviews, 24(1), 71–109. doi:10.1128/CMR.00030-10
8. Wright G.D ,(2011), Molecular mechanisms of antibiotic resistance, chem.
Commun, 47, 4055-4061