Transcript RTA3

F1-3999
The Activity of RTA-3, a Novel Antimicrobial Peptide, Against
Staphylococcus aureus (SA) of Various Resistance Phenotypes
48th Interscience Conference on
Antimicrobial Agents and
Chemotherapy
October 25-28, 2008.
Washington, DC
M. Wootton1, T. Caetano3, C. Dempsey4, A. Hawrani4, T. R. Walsh2 and R. A Howe1
1NPHS
Introduction
Staphylococcus
aureus
(SA)
infections cause serious disease in
the community and hospitals worldwide.
The
establishment
and
emergence of resistance phenotypes
to meticillin (M) and glycopeptides,
including vancomycin and teicoplanin
makes demands upon treatment
options and the health budget. RTA3 is a 16 amino acid antimicrobial
peptide derived from a peptide
produced by Streptococcus mitis. It
has been developed to optimise
activity against multiply resistant
Gram
negatives
including
Pseudomonas
aeruginosa,
Acinetbacter
spp.,
and
Stenotrophomonas maltophilia. The
current study assesses the activity of
RTA-3 against SA with different
susceptibilities to M or vancomycin
(V) using modified in-vitro testing.
Figure: RTA-3 binding to negatively
charged membranes
Microbiology, University Hospital Wales, Cardiff, UK. 2Cardiff University, Cardiff, UK. 3Departamento
de Biologia, Universidade de Aveiro, Portugal; 4Bristol University, Bristol, UK
Materials and Methods
Results
48
. SA strains were tested (Table 1):
12 M sensitive, V sensitive (MSSA),
12 M resistant/V sensitive (MRSA),
12 hetero-V intermediate resistant
(hGISA), 12 V intermediate (GISA)
from an international collection.
Susceptibility was determined by
microbroth and agar dilution using
CLSI
standards,
Mueller-Hinton
media was solidified with agarose.
Minimum inhibitory concentrations
(MIC) were calculated and compared.
The MICs were comparable between
microbroth and agar dilution,
suggesting the agarose modification
for agar dilution was acceptable.
Table 2 shows susceptibilities to
RTA-3 (mg/L) plus MIC50 and
MIC90s for the 48 strains tested.
MSSA strains appeared the most
susceptible. Glycopeptide sensitive
and
intermediate
phenotypes
exhibited similar MICs
2349
2350
2351
2352
2353
2354
2355
2358
2359
2364
2366
2371
96
97
98
99
100
101
102
103
104
105
3463
3911
FOX DD VAN MIC
MSSA
S
1.5
S
1.5
S
1.5
S
1.5
S
1.5
S
2
S
1.5
S
1.5
S
1.5
S
1.5
S
2
S
1.5
MRSA/GSSA
R
0.75
R
0.75
R
0.75
R
0.75
R
0.5
R
1
R
0.75
R
0.75
R
0.5
R
1
R
0.5
R
0.5
PAP-AUC
Strain No
FOX DD
0.65
0.5
0.6
0.52
0.51
0.43
0.4
0.5
0.43
0.41
0.55
0.45
59
60
61
77
119
121
123
124
125
126
127
8
R
R
R
R
R
R
R
R
R
R
R
R
0.54
0.4
0.37
0.44
0.41
0.56
0.5
0.47
0.41
0.54
0.55
0.62
83
84
85
86
106
110
111
112
113
114
115
116
R
R
R
R
R
R
R
R
R
R
R
R
VAN MIC
hGISA
2
2
2
2
2
2
2
6
2
2
2
2
GISA
8
8
8
8
8
8
8
8
8
8
8
8
MSSA
MRSA
hVISA
VISA
MIC50
16
64
32
64
MIC90
>64
64
64
>64
Range
8->64
16-64
16-64
8->64
Conclusions
Table 1: Phenotypic characteristics of strains used
Strain No
Table 2: MIC range, MIC50 and MIC90
for RTA-3 against MSSA, MRSA, hGISA
and GISA
PAP-AUC
0.98
0.98
1.24
1
1.1
1.04
1.14
1.06
1.16
0.98
1.06
1.14
1.8
1.92
1.34
1.32
1.6
1.43
1.41
1.4
1.57
1.47
3.01
1.92
• MICs were generally between 8 –
64mg/L, with GISA and MSSA
showing the most susceptibility.
• These results are encouraging for the
further modification of the peptide to
optimise activity against S. aureus.
• The finding of activity against Gram
positive organisms supports the
hypothesis that RTA-3 has an extra
site of action in addition to the Gram
negative outer membrane.
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