Multidrug resistance (MDR) is a major healthcare concern triggered by the extended subtherapeutic clinical conduct of infectious diseases. Resistant infections are responsible for the death of more than 0.7 million people every year and accordingly, the expected rate of death of people from drug resistant infections in 2050 is 10 million/ year. As Pakistan is among the least spending nations on healthcare all round the world, these epidemics may result in a complete disaster; and since infectious diseases respect no borders, this could circumvent other countries too. Different strategies have been explored to address this healthcare issue including the combinatorial use of a variety of antibiotics, combination treatments of drugs and nanoparticles and the use of drug-conjugated nanoparticles. Most of these strategies show improved antibacterial properties but chances of developing resistance against them is predictable due to the use of previously resistant drugs. Nanoscale manipulation of metal nanoparticles has a notable potential to address this concern by tuning of nano−bio interface to attack bacteria. Among the metals explored, Ag is the most effective and least explored antimicrobial in nano form. The antibacterial strength of silver is due to certain physicochemical and morphological factors, which when rightly tuned could benefit against numerous pathogenic bacteria by giving broad-spectrum killing profile.

In this regard, branched polyethylenimine-decorated silver nanoclusters (bPEI−Ag NCs) were produced to kill MDR pathogenic bacteria selectively by coupling the antimicrobic potential of silver with the selective virulance of bPEI towards bacteria. The small size (~2 nm), stable nature (more than a month), organic capping (PEI), compact coating, selective targeting (electrostatically), sustained discharge of Ag+ ions and the positive surface potential (+30mV) are the key attributes of these Ag nanoclusters to demonstrate their ability to kill different MDR bacterial strains. These Ag NCs were found very effective to kill 12 MDR clinical bacterial strains (uropathogenic) at minimal concentration of ~1 nM compared to human fibroblast and red blood cells.

The dreadful pathogens i.e., P. aeruginosa further challenge the situation of MDR by their innate ability to form biofilms. In another strategy, decrease of bacterial action and virulence through the network of extracellular amyloids was explored with silver nanoclusters (AgNCs) and nanoparticles (AgNPs) having same surface chemistry. The comparative study of these nanomaterials revealed that with the change in surface charge and size of nanoparticles, their bactericidal and antibiofilm properties can be tuned. Compared with the ultrasmall AgNCs, AgNPs entail stronger binding to suppress the fibrillization of FapC, a major protein constituent of the extracellular amyloid matrix of P. aeruginosa. It was further observed that at concentrations of 1 µM or lower, both the bactericidal and antibiofilm potential of nanomaterials was linked with their structure based bio–nano communications but not with the discharge of silver ions. This study demonstrated the biocidal ability of safe nanotechnology through the unique direction of amyloidosis inhibition.

Pneumococcal pneumonia is the most widespread community-acquired and childhood pneumonia. It kills almost 1 million children each year, and more than 80% of these deaths are children under 2 years of age. It is the top most infectious killer of children under the age of 5 in Pakistan. As a result of prevalence of such pathogenic bacteria and the change in their susceptibility to routinely used antimicrobials, there is a dire need for a multi-pronged magic bullet to target Multidrug resistance. In yet another study, this emerging health issue related to MDR in pneumococcal cells was addressed by the design/development of smart and effective nanocapsules encapsulating antibiotic and silver NCs coated with organic ligands to guide the nanocapsules to the desired target. These Ag NCps were synthesized using emulsion stabilization method and were quite stable with 20% of drug loading efficiency. These nanocapsules have shown their potential of efficient targeting, delivering and retaining hydrophobic drug in the desired pneumococcal strains by breaking resistive barriers at concentrations safe to mammalians cells. This method is quite simple and easy to modify according to specific application.

Overall, this work supplement the available literature and suggests that silver based nanomaterials are being recognized as starting point for the development of novel inorganic materials based potential antibiotic candidates to address MDR. Various other aspects are also elaborated in the publications (cited below) emerging out of the thesis.