Cocktail of CuO, ZnO, or CuZn Nanoparticles and Antibiotics for Combating Multidrug-Resistant Pseudomonas aeruginosa via Efflux Pump Inhibition

Abstract

Multidrug resistant (MDR) bacteria have become an extremely serious public health concern. Bacteria can develop resistance through various mechanisms. Drug extrusion by the multidrug efflux pumps represents an important mechanism of antimicrobial resistance. Inhibitors of bacterial efflux pumps as adjuvants in antibacterial therapy are a reasonable and cost-effective pursuit since the shortage of antibiotics threatens global human health. Combined use of inorganic nanoparticles (NPs) with conventional antibiotics constitutes a promising alternative for fighting antibiotic resistance as NPs could restore the activity of the existing antibiotics. In the present study, the potential role of polyol-coated CuO, ZnO, and CuZn NPs as efflux pump inhibitors has been investigated against MDR clinical strains of Pseudomonas aeruginosa. The mode of action of the NPs was evaluated by studying their synergistic activity in combination with the antibiotics meropenem and ciprofloxacin, and their efflux inhibitory activity was studied by real-time fluorometry and a cartwheel assay. The results showed that the NPs act synergistically, in a concentration-dependent manner, with antibiotics known to be subject to efflux. Furthermore, the killing effect of the synergistic combinations over time was determined by time–kill studies. All the NPs at the lowest tested concentration enhanced the antibacterial activity of ciprofloxacin, as it was evidenced by both checkerboard and time–kill assays. Real-time fluorometric analyses revealed that NPs at sub-inhibitory concentrations promote the intracellular accumulation of ethidium bromide (EtBr). The EtBr agar cartwheel method showed that the NPs at the sub-minimum inhibitory concentration increased the fluorescence even at lower concentrations of EtBr, whereas in the absence of NPs, there was a much lower fluorescence. These results suggest that NPs may serve as potential sources of efflux pump inhibitors in order to tackle antimicrobial resistance.

Towards rational nanomaterial design by predicting drug–nanoparticle system interaction vs. bacterial metabolic networks

“…The revision includes a total of 65 studies that found positive DADNP instances in a total of 21 papers. 94–114 We collected 102 reports of DADNP complex tests with at least one favorable experimental outcome from these journals. The size of the NP used to build the DADNP complexes ranges from 5 nm to 100 nm.…”

“…The DADNP design incorporates coating agents that may aid boosting the complexes' stability and/or bioavailability over time. 94–114…”

“…In any case, the DADNP complexes discovered contained a wide set of ADs, including PEN (ampicillin, meropenem, and imipenem), TETRA (tetracycline), MACRO (gentamicin, vancomycin, and rifampicin), QUIN (ofloxacin and ciprofloxacin), aminoglycoside (tobramycin, kanamycin, and streptomycin), amphenicols (chloramphenicol), lipopeptide (daptomycin), and polypeptide (polymyxin B). 34,78–97…”

“…In any case, the DADNP complexes discovered contained a wide set of ADs, including PEN (ampicillin, meropenem, and imipenem), TETRA (tetracycline), MACRO (gentamicin, vancomycin, and rifampicin), QUIN (ofloxacin and ciprofloxacin), aminoglycoside (tobramycin, kanamycin, and streptomycin), amphenicols (chloramphenicol), lipopeptide (daptomycin), and polypeptide (polymyxin B). 34,[78][79][80][81][82][83][84][85][86][87][88][89][90][91][92][93][94][95][96][97] We may infer that this experimental collection of DADNP complex preclinical experiments contains a significant degree of structural and biological variety. Our initial collection of AD and NP assays vs. MN used to assemble putative DADNP complexes was sampled intentinally with significant structural The study of the interaction of the physical properties of conjugated nanoparticles with antibacterial drugs vs. the various metabolic networks of microorganisms could have an impact on the reduction of costs and environmental impacts.…”

Te–Cefotaxime nanocomposites with restored antibiotic susceptibility and the LED light activated photothermal effect for rapid MRSA eradication

“…14 In our group, nanosized Bi 2 S 3 was found to restore the activity of gentamicin against MRSA partly. 15 Possible mechanisms for restoring the susceptibility of ineffective antibiotics by inorganic nanomaterials have been reported, such as (1) inhibiting β-lactamase and preventing hydrolysis of β-lactam antibiotics by drug-resistant bacteria; 16 (2) inhibiting the efflux pump and preventing the extrusion of antibiotics in drug-resistant bacteria; 17 and (3) damaging the membrane permeability and promoting the antibiotic uptake. 18…”