Abstract
Bacterial drug resistance has emerged as a serious global threat mandating the development of novel methodologies that allow facile modulation of antimicrobial action in a controlled fashion. Conjugating antibiotics to nanoparticles helps to meet this goal by increasing the drug’s overall avidity, bioavailability and easier internalisation into mammalian cells, targeting bacteria that otherwise escape antibacterial action by host cell-localisation. We used polymyxin B sulfate (PMB) and sushi peptide as model drugs against Gram-negative bacteria and established their enhanced antimicrobial activity on Escherichia coli (E. coli) cells after conjugation to gold nanoparticles (AuNPs). The efficacy of the bioconjugates was also tested on Salmonella typhi (S. typhi) bacteria infected into cervical cancer cells (HeLa) and further improved through specific targeting via folate receptors. Our results demonstrate significantly lower inhibitory concentration values for sushi-NP assemblies as compared to free drug, especially at optimal drug loading levels. No major cytotoxicity was observed in mammalian cells alone.
Highlights
Antibiotics are the most conventional therapeutics used for the treatment of bacterial infections, 50% of these drugs prescribed to humans are either not needed or not effectively utilized as prescribed
after conjugation to gold nanoparticles (AuNPs) were synthesized, and their morphology, size and stability was characterized by different techniques including transmission electron microscopy (TEM) (Fig. 2A) and UV-Visible spectroscopy (Figs 2B, S3A), which showed that the particles were fairly spherical, monodisperse (16 ± 4 nm) and stable for several months when stored at 4 °C
The binding of polymyxin B sulfate (PMB), sushi and folic acid to AuNPs was qualitatively confirmed by FTIR (Fig. S1)
Summary
Antibiotics are the most conventional therapeutics used for the treatment of bacterial infections, 50% of these drugs prescribed to humans are either not needed or not effectively utilized as prescribed. Conventional antibiotics suffer from several issues such as improper biodistribution, poor water solubility, lack of target specificity and loss of efficacy over time due to the emergence of drug resistance in pathogenic bacteria[2]. The structure-property relationship studies for these drugs illustrate that while PMB acts by neutralizing and shedding off the cell wall component lipopolysaccharide (LPS) present on the outer cell wall of all Gram-negative bacteria[21], sushi uses LPS as a latch and lyses the bacteria by disrupting the membrane and releasing its cytosolic content, without LPS leakage[22] This may be beneficial as free LPS in the bloodstream is known to cause medical complications such as sepsis. The extent of drug loading was found to be a crucial factor in modulating the particle’s antibacterial activity
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