1. 1. Abstract 3. Objective of the study 4. Methods 5. Results
Class II HMG-CoA Reductase Inhibitors targeting multi-drug resistant Staphylococcus aureus
Waleed Yonis1,4, Shankar Thangamani1, Matthew Hostetler 2, ‎Daneli López-Pérez2, Calvin Steussy3, Mark Lipton2, Cynthia Stauffacher3, Mohamed Wael Abd Al-Azeem4 and Mohamed Seleem1
1 Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN
2 Department of Chemistry, Purdue University, West Lafayette, IN
3 Department of Biological Sciences Purdue University, West Lafayette, IN
4 Faculty of Veterinary Medicine, Microbiology Department, South Valley University, Egypt
1. Abstract
3. Objective of the study
Table (3) show effect of Treatment of C. elegans infected with MRSA by the 3 Analogues
Development of HMG-CoA inhibitors as a novel antibiotic for the treatment of multidrug-resistant staphylococcal infections.
The emergence of multidrug-resistant bacterial infections such as methicillin-resistant Staphylococcus aureus (MRSA) has become a global epidemic. Therefore new antibiotics that target novel pathways within resistant pathogens are in urgent need to treat such infections. A possible novel target in Gram-positive cocci is class II HMG-CoA reductase (HMGR), part of the mevalonate pathway, which is essential for growth and multiplication of S. aureus. We have synthesized and tested novel HMG-CoA inhibitors that showed potent activity towards the bacterial HMGRs. The novel compounds showed activity, in low micromolar concentration, against MRSA and vancomycin-resistant S. aureus (VRSA). We demonstrated antimicrobial activity of these compounds against MRSA in vivo in a unique infection whole animal model using the nematode Caenorhabditis elegans. Furthermore, therapeutic efficacy of these compounds was also evaluated in a mouse-model of staphylococcal skin infection. HMGR inhibitor at 2% concentration significantly reduced the bacterial load in skin lesion infected with MRSA USA300. This study provide evidence that these compounds showing promise as a novel treatment for MRSA infections and lay the foundation for further analysis and development of HMGR inhibitors as a potential treatment for multidrug-resistant staphylococcal infections.
Treatment
Log CFU/worm
Log Reduction
DMSO control
5.04 ± 0.10
0.00 1
2.33 ± 0.09
2.71* 2
2.20 ± 0.43
2.84* 3
1.80 ± 0.10
3.24*
Vancomycin
3.26 ± 0.20
1.78*
4. Methods
In this study, 22 novel bacterial HMGR inhibitors were screened for its in vitro antimicrobial activity against methicillin resistant Staphylococcus aureus (MRSA) .
In vivo antimicrobial activity was tested against MRSA using the nematode Caenorhabditis elegans and mouse model.
The 3 Analogues showing a potent log reduction of MRSA in C.elegans infection model.
MRSA Skin infection
3 groups of mice (n=5) were infected intradermal with 9x108 MRSA USA h after infection, one group was given 20 mg/mouse vehicle Lipoderm (control), one group was giving 20 mg/mouse of 2% mupirocin/Lipoderm and the third group was given 20 mg/mouse of 2 % Analogue 1 in Lipoderm. The mice were treated for 4 days (4 doses) and euthanized 24 h after the last treatment.
5. Results
Table (1) : show 3 analogues which have promising antibacterial activity against MRSA
Analogue
MRSA MIC/MBC (µM) 1
16/16 2
32/32 3
64/64
2. Introduction
Antibiotic resistant pathogenic bacteria such as methicillin resistant Staphylococcus aureus (MRSA) and vancomycin resistant staphylococcus aureus (VRSA) are the most common causes of hospital-acquired (nosocomial) infections in the United States and Europe.
Nosocomial infections cause tens of thousands of deaths annually and result in billions of dollars in additional health care costs in the US, alone needed.
Antibiotics currently used to treat these infections frequently cause nausea, vomiting, and diarrhea. Because these antibiotics are not specific for the pathogenic bacteria and kill normal flora, i.e., commensal bacteria, treatment of infections often causes oral, intestinal, or genital infections due to fungal overgrowth.
Furthermore, antibiotics used to treat antibiotic resistant bacteria, such as vancomycin, have adverse side effects, including nephrotoxicity. ** **
From the previous table the most promising compound was analogue 1 so we detected the MIC50 and MIC 90 against MRSRA and VRSA in table (2)
Bacteria
Number of isolates
Analogue 1 (µm)
MIC50
MIC 90
Methicillin resistant S. aureus MRSA (21) 32 16
Vancomycin resistant S.aureus VRSA (15) 8
Analogue 1 ( 2%)
6. Conclusion
HMG-CoA inhibitors showing promise as a novel treatment for multi-drug resistant staphylococcal infections .
Table 2 show that The analogue 1 has potent antimicrobial activity against MRSA and VRSA with range 32 and 16 µm for MRSA and 16 and 8 for VRSA.