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Inhibition of Drug Resistance of Staphylococcus aureus by Efflux Pump Inhibitor and Autolysis Inducer to Strengthen the Antibacterial Activity of β-lactam Drugs

Polish Journal of Microbiology
Volume 68 (2019): Issue 4 (January 2019)
By:
Open Access
|Dec 2019

Figures & Tables

Fig. 1A i 1B.

Clinical observations of mammary tissue of mouse infected with Staphylococcus aureus ATCC 29213 or MRSA135 before and after treatment with the drugs.
Clinical observations of mammary tissue of mouse infected with Staphylococcus aureus ATCC 29213 or MRSA135 before and after treatment with the drugs.

Fig. 1C.

Clinical observations of mammary tissue of mouse infected with Staphylococcus aureus ATCC 29213 or MRSA135 before and after treatment with the drugs.
Clinical observations of mammary tissue of mouse infected with Staphylococcus aureus ATCC 29213 or MRSA135 before and after treatment with the drugs.

Fig. 2.

Histopathological observations for each group of mice (control, infected, and treated with the drugs).
Histopathological observations for each group of mice (control, infected, and treated with the drugs).

Fig. 3A i 3B

Fig. 3.

The culture of Staphylococcus aureus isolated from each group of mice (control, infected, treated with the drugs).MCZ – miconazole; TZ – thioridazine; CXN – cloxacillin; MCZ + TZ + CXN – the combination of miconazole, thioridazine, cloxacillin. There was no significant difference between the cloxacillin-treated and three-drugs-treated mice (P = 0.5649). The * on the horizontal line indicates a significant difference analysis between the CXN group and the three-drug group.* P < 0.05, ** p < 0.01, *** p < 0.0001.
The culture of Staphylococcus aureus isolated from each group of mice (control, infected, treated with the drugs).MCZ – miconazole; TZ – thioridazine; CXN – cloxacillin; MCZ + TZ + CXN – the combination of miconazole, thioridazine, cloxacillin. There was no significant difference between the cloxacillin-treated and three-drugs-treated mice (P = 0.5649). The * on the horizontal line indicates a significant difference analysis between the CXN group and the three-drug group.* P < 0.05, ** p < 0.01, *** p < 0.0001.

Fig. 4.

Drug effects on the cytokine level in mouse mastitis models.(A) Serum IFN-γ level in mice infected with ATCC 29213; (B) Serum IFN-γ level in mice infected with MRSA135; (C) Serum IL-6 level in mice infected with ATCC 29213; (D) Serum IL-6 level in mice infected with MRSA135; (E) Serum TNF-α level in mice infected with ATCC 29213; (F) Serum TNF-α level in mice infected with MRSA135; MCZ – miconazole; TZ – thioridazine; CXN – cloxacillin; MCZ + TZ + CXN – combination of miconazole, thioridazine, cloxacillin. The * on the horizontal line indicates a significant difference analysis between the CXN group and the three-drug group. * P < 0.05, **p < 0.01, ***p < 0.0001.
Drug effects on the cytokine level in mouse mastitis models.(A) Serum IFN-γ level in mice infected with ATCC 29213; (B) Serum IFN-γ level in mice infected with MRSA135; (C) Serum IL-6 level in mice infected with ATCC 29213; (D) Serum IL-6 level in mice infected with MRSA135; (E) Serum TNF-α level in mice infected with ATCC 29213; (F) Serum TNF-α level in mice infected with MRSA135; MCZ – miconazole; TZ – thioridazine; CXN – cloxacillin; MCZ + TZ + CXN – combination of miconazole, thioridazine, cloxacillin. The * on the horizontal line indicates a significant difference analysis between the CXN group and the three-drug group. * P < 0.05, **p < 0.01, ***p < 0.0001.

The activity of the combination of cloxacillin and miconazole against Staphylococcus aureus strains in vitro_

StrainsFICI
MRSA140.63
MRSA150.75
MRSA160.38
MRSA200.31
MRSA210.31
MRSA222.25
MRSA250.53
MRSA292.13
MRSA300.26
MRSA640.14
MRSA650.26
MRSA751.00
MRSA761.13
MRSA920.26
MRSA940.51
MRSA970.52
MRSA980.26
MRSA1250.50
MRSA1261.50
MRSA1341.50
MRSA1350.27
MRSA1421.01
MRSA1620.63
ATCC 292130.50
MSSA100.56
MSSA130.31
MSSA142.00
MSSA311.13
MSSA362.02
MSSA411.50
MSSA420.27
MSSA441.06
MSSA501.03
MSSA511.00
MSSA541.50
MSSA561.00
MSSA621.50
MSSA651.03
MSSA660.53
MSSA670.31
MSSA680.53
MSSA700.52
MSSA720.28
MSSA731.03
MSSA781.06
MSSA790.56
MSSA800.56

j_pjm-2019-047_tab_007

MRSA(methicillin-resistant S. aureus);
TZ(thioridazine);
MCZ(miconazole);
CXN(cloxacillin);
MIC(the minimum inhibitory concentration);
TNF-α(tumor necrosis factor-α);
IL-1β(interleukin 1β);
IL-6(interleukin 6);
IĸB(K-B inhibitor);
NF-KB(nuclear factor K-B);
CTCC(the China Type Culture Collection);
ATCC(American Type Culture Collection);
FIC(the fractional inhibitory concentration).

The activity of the combination of cloxacillin and thioridazine against Staphylococcus aureus strains in vitro_

StrainFICI
MRSA140.38
MRSA150.63
MRSA160.75
MRSA200.25
MRSA210.50
MRSA220.63
MRSA250.31
MRSA290.19
MRSA301.06
MRSA640.25
MRSA650.25
MRSA751.13
MRSA761.13
MRSA920.31
MRSA940.19
MRSA970.25
MRSA980.19
MRSA1250.27
MRSA1260.50
MRSA1340.16
MRSA1350.16
MRSA1420.63
MRSA1620.38
ATCC 292130.28
MSSA100.31
MSSA130.56
MSSA140.63
MSSA310.63
MSSA360.38
MSSA410.63
MSSA420.56
MSSA440.38
MSSA500.38
MSSA510.14
MSSA540.38
MSSA560.63
MSSA620.63
MSSA650.63
MSSA661.13
MSSA671.13
MSSA681.13
MSSA701.13
MSSA721.06
MSSA730.63
MSSA781.25
MSSA791.25
MSSA800.25

The MICs values of individual antimicrobial agents against Staphylococcus aureus isolates_

Antimicrobial agentsMIC (μg/ml)
Range50%90%
Cloxacillin4–51216512
Thioridazine16–643264
Miconazole1–848

Summary of thioridazine, miconazole and cloxacillin activity in combination (expressed as the MIC value) against Staphylococcus aureus strains_

Antimicrobial agentsMIC (μg/ml)
Range50%90%
CloxacillinThioridazine0.125–51216512
Miconazole0.25–5124512
Thioridazine + Miconazole0.000972–160.58

The activity of the combination of cloxacillin, thioridazine, and miconazole against MRSA strains in vitro_

StrainCXNTZMCZCXNTZMCZFICI
MICs (Single)MICs (Synergy)
MRSA14512322440.250.26
MRSA15512322240.250.25
MRSA16512164140.250.31
MRSA202563220.2540.250.25
MRSA211281640.540.250.32
MRSA22643240.2540.500.25
MRSA255121620.540.500.50
MRSA29256644440.500.20
MRSA305126440.540.500.19
MRSA64512328840.500.20
MRSA655123240.540.500.25
MRSA755123220.540.500.38
MRSA76512324840.500.27
MRSA925121640.007840.500.38
MRSA945123220.007840.500.38
MRSA972563220.015640.500.38
MRSA985123240.007840.500.25
MRSA1252561620.540.500.50
MRSA126256161140.500.75
MRSA1345123210.007840.500.63
MRSA1352563240.2540.500.25
MRSA142512321240.500.63
MRSA1625123241640.500.28
ATCC 2921341640.015640.500.38

The activity of the combination of cloxacillin, thioridazine, and miconazole against MSSA strains in vitro_

StrainCXNTZMCZCXNTZMCZFICI
MICs (Single)MICs (Synergy)
MSSA1016644440.250.38
MSSA138648840.251.09
MSSA148322840.251.25
MSSA3116322440.250.50
MSSA36163210.01562540.250.38
MSSA418321440.250.88
MSSA42166480.12540.250.10
MSSA44163210.540.250.41
MSSA50163210.12540.250.38
MSSA51163220.00197540.250.25
MSSA54161620.062540.250.38
MSSA56163220.0312540.250.25
MSSA62163220.000971540.250.25
MSSA65163220.12540.250.26
MSSA6616324440.250.44
MSSA6716324840.250.69
MSSA68163241640.251.19
MSSA70163240.01562540.250.19
MSSA72166480.540.250.13
MSSA73163220.062540.250.25
MSSA7881620.0312540.250.38
MSSA7981640.0312540.250.32
MSSA80163240.007812540.250.19
ATCC 2921341640.015640.500.38
DOI: https://doi.org/10.33073/pjm-2019-047 | Journal eISSN: 2544-4646 | Journal ISSN: 1733-1331
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Language: English
Page range: 477 - 491
Submitted on: Jun 20, 2019
Accepted on: Sep 21, 2019
Published on: Dec 5, 2019
Published by: Polish Society of Microbiologists
In partnership with: Paradigm Publishing Services
Publication frequency: 4 times per year
Keywords:
mastitis,
thioridazine (TZ),
miconazole (MCZ),
cloxacillin (CXN),
combination therapy
Related subjects:
Life sciences,
Microbiology and virology

© 2019 WENJING LUAN, XIAOLEI LIU, XUEFEI WANG, YANAN AN, YANG WANG, CHAO WANG, KESHU SHEN, HONGYUE XU, SHULIN LI, MINGYUAN LIU, LU YU, published by Polish Society of Microbiologists
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License.

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