A Novel Ivermectin-Derived Compound D4 and Its Antimicrobial/Biofilm Properties against MRSA

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) and its biofilms infection is still a serious threat to global health. It is urgent to develop efficient drugs by repositioning or designing drugs to solve this problem. In this study, the antibacterial/biofilm activity and mechanisms of ivermectin (D) and its 4′′-position amino substitution derivative (D4) against MRSA were investigated. The minimum inhibitory concentration (MIC) of D was 20 μg/mL, which is four times higher than D4 (MIC = 5 μg/mL). The mechanism research demonstrated that D4 was more potent than D at destroying bacterial cell wall, permeating cell membrane (6.25–36.0% vs 1.92–6.04%) and binding to MRSA genomic DNA. Moreover, after incubation with 10–40 μg/mL D4 for 24 h, the percentages of biofilm decreased by 21.2–92.9%, which was more effective than D (no significant change at 40 μg/mL). The antibiofilm effect is achieved by regulating the expression of related genes (RSH, relQ, rsbU, sigB, spA, and icaD). Additionally, though the higher hemolysis makes D4 a safety risk for intravenous injection, other administration options could be considered as well. Therefore, all the results have indicated that D4 may be a potential candidate compound for the treatment of MRSA and its biofilm infections.

Streptomyces sp.—A Treasure Trove of Weapons to Combat Methicillin-Resistant Staphylococcus aureus Biofilm Associated with Biomedical Devices

“…Remarkably, substituting the 4"-positive hydroxyl group with an amino group resulted in a novel ivermectin-derived compound (D4) that demonstrated an improved antibiofilm activity against MRSA compared to its parent compound. The study further elucidated that D4 may exert anti-MRSA biofilm by downregulating several biofilm formation-related genes, such as spA and icaD, which encode proteins involved in the attachment and biofilm formation of S. aureus [100].…”

“…Another interesting example is ivermectin, which is an FDA-approved antihelminthic drug that has been shown for the first time to possess antibacterial activity against clinical isolates of S. aureus, which include both MSSA and MRSA with a MIC value of 6.25 µg/mL and 12.5 µg/mL, respectively [99]. A number of studies also evaluated its antibiofilm activity against MRSA but did not yield promising results [100,101]. Remarkably, substituting the 4"-positive hydroxyl group with an amino group resulted in a novel ivermectin-derived compound (D4) that demonstrated an improved antibiofilm activity against MRSA compared to its parent compound.…”

Could the COVID-19-Driven Increased Use of Ivermectin Lead to Incidents of Imbalanced Gut Microbiota and Dysbiosis?

“…The authors reported 12.5 µg/mL IVM as minimum inhibitory concentration (MIC) against MRSA, which is double the MIC determined against MSSA (6.25 µg/ml). Tan et al [ 37 ], however, reported bacteriostatic MIC values of 20.0 µg/mL against the methicillin-resistant S. aureus ATCC 43,300. The authors have also shown that a derivative of IVM, with an OH group replaced by an NH 2 group at carbon position 4 (referred to as molecule D4), was much more effective against MRSA and reported a fourfold decrease in MIC values.…”

“…IVM may act in a similar way. Scanning electron microscopy (SEM) images have shown structural changes of cell walls (wrinkles and sagging) when S. aureus cells were exposed to 4 × the MIC of IVM (80 µg/mL) [ 37 ]. This confirmed the hypothesis that IVM interferes with cell wall synthesis.…”

Bioguided Isolation of Antibiofilm and Antibacterial Pregnane Glycosides from Caralluma quadrangula: Disarming Multidrug-Resistant Pathogens

“…The emergence of microbial resistance to numerous conventional antibiotics has become a serious global concern. These microbes cause serious bloodstream infections, urinary tract infections, wound infections, pneumonia, and secondary meningitis with high morbidity and mortality rates [3][4][5]. MRSA and MDRAB are the most commonly encountered pathogens in hospitals [6,7].…”