Transcript Gorman_TIP_MRSA & Chemical Bonding

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:
“Though there are several types of staph infections, the one
causing concern among health professions is methicillinresistant 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
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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%
EM image of S. aureus (Paustian 2006)
(Peacock et al. 2001)
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 of
peptidoglycan monomer.
2. Addition of
pentaglycine cross-linker
3. Transglycosylation
to outside of membrane
4. Transpeptidation to
form 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
OH
L-vancosamine
H2N
CH3
H3C
O
a.
OH
OH
Tyrosine
O
HO
OH
OH
D-glucose
Tyrosine
O
O
O
NH
NH
NH
HN
O
NH
O
Glycines
OH
O
Cl
O
NH
O
O
CH3
O
NH2
Asparagine
Leucine
O
NH2
CH3
Cl
O
HO
HN
H
N
O
H
O
Leucine
OH
N
H
OH
H
H
O
N
H
O
NH
O
HO
CH3
O
NH2
O
OH
HO
H
N
OH
HN
CH3
CH3
Vancomycin - Mechanism
 folds into a bowl shaped
molecule
 C-terminal L-Lys-D-AlaD-Ala fits into this groove
 5 hydrogen bonds are
formed
HO
H2HN3C
OH
CH3
O HO
OH
O
OH
O
O
Cl
Cl
O
O
HO
HO
O
NH
O
N
H
NH O
NH
NH
O
NH
NH2
HO
OH
O
H2N
CH3
O
O
O
HO
OH
H
N
CH3
H3C
CH3
O
NH
-
NH
O
O
CH3
NH2
(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 antibiotics
 What is this class’ common target?
 Sketch the molecular structure of an antibiotic
from this class
 Provide a brief description of the molecular
geometry of this compound and how it interacts
with its target molecule.
Works Cited
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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=13
7.
Peacock, S. J., de Silva, I. & Lowy, F. D. “What determines nasal carriage of Staphylococcus
aureus?” Trends Microbiol. 9 (2001):605–610.