Abstract
Infections caused by methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA) are prevalent. MRSA infections are difficult to treat and there are no new classes of antibiotics produced to the market to treat infections caused by the resistant bacteria. Therefore, using antibiotic enhancers to rescue existing classes of antibiotics is an attractive strategy. Nordihydroguaiaretic acid (NDGA) is an antioxidant compound found in extracts from plant Larrea Tridentata. It exhibits antimicrobial activity and may target bacterial cell membrane. Combination efficacies of NDGA with many classes of antibiotics were examined by chequerboard method against 200 clinical isolates of MRSA and MSSA. NDGA in combination with gentamicin, neomycin, and tobramycin was examined by time-kill assays. The synergistic combinations of NDGA and aminoglycosides were tested in vivo using a murine skin infection model. Calculations of the fractional inhibitory concentration index (FICI) showed that NDGA when combined with gentamicin, neomycin, or tobramycin displayed synergistic activities in more than 97% of MSSA and MRSA, respectively. Time kill analysis demonstrated that NDGA significantly augmented the activities of these aminoglycosides against MRSA and MSSA in vitro and in murine skin infection model. The enhanced activity of NDGA resides on its ability to damage bacterial cell membrane leading to accumulation of the antibiotics inside bacterial cells. We demonstrated that NDGA strongly revived the therapeutic potencies of aminoglycosides in vitro and in vivo. This combinational strategy could contribute major clinical implications to treat antibiotic resistant bacterial infections.
Highlights
There is no doubt that antimicrobial discovery and development experienced an era of prosperity in the not so distant past, known as the “golden era of antibiotics” (Aminov, 2010)
Synergistic activities were only observed when Nordihydroguaiaretic acid (NDGA) was combined with gentamicin, neomycin, and tobramycin for both Methicillin-sensitive S. aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA)
We showed that NDGA boosted the antibacterial efficacies of aminoglycosides, namely gentamicin, neomycin, and tobramycin, against MSSA and MRSA both in vitro and in a mouse infection model
Summary
There is no doubt that antimicrobial discovery and development experienced an era of prosperity in the not so distant past, known as the “golden era of antibiotics” (Aminov, 2010) This era of prosperity has come to an end due to rapid emergence of antibiotic resistance in bacteria and a dramatically reduced rate in discovery of new antibiotic classes (Sheridan, 2005). Some cases of MRSA infections are resistant to vancomycin (Liu and Chambers, 2003) and linezolid resistance has recently emerged (Gu et al, 2013). The potential that the anti-staphylococcal activities of aminoglycosides offer makes them an attractive option Revival of this class in treatment of MRSA would allow reduced vancomycin usage which ideally should only be used as a last resort
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