MRSA Treatment and Molecular Geometry/ Bonding
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Transcript of MRSA Treatment and Molecular Geometry/ Bonding
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MRSA Treatment andMolecular Geometry/ Bonding
Pharmaceutical Chemistry TIP
By: James Gorman
Dr. Philip Deshong
University of Maryland
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Warm-up Activity
Comment on the following:
“Though there are several types of staph infections, the one causing concern among health professions is methicillin-resistant staphylococcus aureus, or MRSA, a bacterium that is resistant to certain types of antibiotics. Several cases of MRSA have been confirmed in Massachusetts this fall, including schools in Winchester and Wrentham.”
(Lefferts, Jennifer F. 2007)
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Overview
Prevalence of Staphylococcus aureus Cell Wall - Importance and Structure Cell Wall - Construction Cell Wall – Antibiotic target Overview of methicillin resistance Vancomycin Vancomycin resistance
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S. aureus Prevalence
% Nasal Colonization of Population Permanently - 20% Transient - 60% Never- 20%
(Peacock et al. 2001)
EM image of S. aureus (Paustian 2006)
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Cell Wall – Importance & Structure
Mechanically supports the more flimsy cell membrane.
20-40 nm thick Composed of
Peptidoglycans Teichoic acids Surface proteins
(Todar 2005)
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Cell Wall – Construction
1. Construction ofpeptidoglycan monomer.2. Addition ofpentaglycine cross-linker3. Transglycosylationto outside of membrane4. Transpeptidation toform cell wall
(Fluit and Schmitz 2003)
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Peptidoglycan Activity
See hand out for hands-on activity
Dmitriev 2004
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Peptidoglycan Cross-linking
Glycan chain adopts helical structure allowing the pentapeptide chains to adopt a zigzag conformation facilitating the construction of a scaffold-like cell wall structure
(Dmitriev 2004)
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Cell Wall – Antibiotic Target
-lactams compete with the D-Ala-D-Ala portion of peptidoglycan inhibiting cross-linking.
Bacteria fight back
by degrading -lactam
ring
http://sitemaker.umich.edu/medchem9/penicillin_pharmacology
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Vancomycin – “Drug of Last Resort”
Vancomycin is a peptide-based antibiotic produced by Amycolatopsis orientalis, a soil bacteria. Unlike -lactams, it cannot be administered orally but by IV. Toxic compound which requires blood levels to be constantly monitored in the hospital.
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Vancomycin Hands-on Activity
See hand out
CH3
CH3NH2
O
NHNH
O
OH
NH2
O
O
NHNH
O
NH
O
O
NH
OH
OHO
a.
Leucine
Tyrosine
AsparagineLeucine
Glycines
Tyrosine
H
H
ClO
O O
NH
OH
Cl
NH
O
NH
ONH
O
OHOHOH
OH
O
NH
NH2
O O
NH
OH
O
NH
H
CH3
CH3
CH3
O
O
OOH
OHOH
CH3
OH
NH2
CH3
OH
L-vancosamine
D-glucose
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Vancomycin - Mechanism
folds into a bowl shaped
molecule C-terminal L-Lys-D-Ala-
D-Ala fits into this groove 5 hydrogen bonds are
formed
Cl O O O
N H
O H
Cl
N H O N H
O N H O
O H O H
O H
O H
O
N H
N H 2
O O
N H O H
O N H C H 3
C H 3
C H 3
O
O
O O H O H
O H
C H 3 O H N H 2 C H 3
O H
O N H 2
N H 2
N H O
C H 3 N H
O
C H 3 O -
(Knox et al. 1990)
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Vancomycin - Resistance Naturally found in vancomycin producing bacteria as a set of 3 genes (VanA, H, and X) Involves replacement of terminal D-Ala with D-lactate
(Lessard and Walsh’s 1999)
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VanX Mechanism
Zn(II)-containing metalloenzyme which removes the terminal D-Ala.
(Mathews 2006)
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Effect of D-Lactate 1000 fold reduction in affinity!!! Structurally
Amine linking the D-Ala’s changes to ketone Bonding
Eliminates a hydrogen bond Introduces lone pair repulsion between carbonyl
groups.
Hands-on- Produce this molecular change in peptidoglycan and point out the changes.
(Bugg et al. 1991)
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Homework Assignment Internet Research
Name one other class antibioticsWhat is this class’ common target?Sketch the molecular structure of an antibiotic
from this classProvide a brief description of the molecular
geometry of this compound and how it interacts with its target molecule.
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Works Cited Bugg, Timothy; G. Wright, S. Dutka-Malen, M. Arthur, P. Courvailin, and C. Walsh. “Molecular
Basis for Vancomycin Resistance in Enterococcus faecium BM4147: Biosynthesis of Depsipeptide Peptidoglycan Precursor by Vancomycin Resistance Proteins VanH and VanA.” Biochemistry 30 (1991):10408-10415.
Dmitriev, Boris A., Filip V. Toukach, O. Holst, E. T. Rietschel, and S. Ehlers. “Tertiary Structure of Staphylococcus aureus Cell Wall Murein.” Journal of Bacteriology 2004:7141–7148.
Lefferts, Jennifer F. “Schools trying to stay ahead of staph infections.” The Boston Globe Nov. 11, 2007: A.
Lessard, Ivan; Walsh, Christopher. “VanX, a bacterial D-alanyl-D-alanine dipeptidase: Resistance, immunity, or survival function?” Proc. Natl. Aced. Sci. 96 1999:11028-11032.
Knox, James R. and R. F. Pratt Antimicrobial Agents and Chemotherapy. 34(7) 1990:1342-1347. Paustian, T, comp. Microbiology and Bacteriology: the World of Microbes. 2006. 31 Dec. 2007
http://www.bact.wisc.edu/Microtextbook/index.php?module=Book&func=displayarticle&art_id=137.
Peacock, S. J., de Silva, I. & Lowy, F. D. “What determines nasal carriage of Staphylococcus aureus?” Trends Microbiol. 9 (2001):605–610.