mrsa treatment and molecular geometry/ bonding
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MRSA Treatment and Molecular Geometry/ Bonding. Pharmaceutical Chemistry TIP By: James Gorman Dr. Philip Deshong University of Maryland. Warm-up Activity. Comment on the following: - PowerPoint PPT PresentationTRANSCRIPT
MRSA Treatment andMolecular Geometry/ Bonding
Pharmaceutical Chemistry TIP
By: James Gorman
Dr. Philip Deshong
University of Maryland
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)
Overview
Prevalence of Staphylococcus aureus Cell Wall - Importance and Structure Cell Wall - Construction Cell Wall – Antibiotic target Overview of methicillin resistance Vancomycin Vancomycin resistance
S. aureus Prevalence
% Nasal Colonization of Population Permanently - 20% Transient - 60% Never- 20%
(Peacock et al. 2001)
EM image of S. aureus (Paustian 2006)
Cell Wall – Importance & Structure
Mechanically supports the more flimsy cell membrane.
20-40 nm thick Composed of
Peptidoglycans Teichoic acids Surface proteins
(Todar 2005)
Cell Wall – Construction
1. Construction ofpeptidoglycan monomer.2. Addition ofpentaglycine cross-linker3. Transglycosylationto outside of membrane4. Transpeptidation toform cell wall
(Fluit and Schmitz 2003)
Peptidoglycan Activity
See hand out for hands-on activity
Dmitriev 2004
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)
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
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.
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
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)
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)
VanX Mechanism
Zn(II)-containing metalloenzyme which removes the terminal D-Ala.
(Mathews 2006)
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)
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.
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.