Nanotechnology as a therapeutic tool to combat microbial resistance☆
Graphical abstract
Introduction
For many years, antimicrobial drugs have been used to inhibit or kill bacteria and other microbes. However, microbial resistance to these drugs has developed on a very large scale over time, greatly reducing their effectiveness, and is an ever growing problem [1]. One of the most promising strategies for overcoming microbial resistance is the use of nanoparticles.
This review article consists of three parts: The first part discusses the epidemiology of microbial resistance. The second part discusses development of resistance and specific mechanisms of resistance [1]. These include, among others, decreased uptake and increased efflux of drug from the bacterial cell [2]; expression of resistance genes that code for an altered version of the substrate to which the antimicrobial agent binds [3], [4]; and covalent modification of the antibiotic molecule which inactivates its antimicrobial activity [2]. In addition, bacteria can avoid contact with antibiotics by forming biofilms and by intracellular activity [5], [6], [2].
The third part of this review discusses mechanisms by which nanoparticles combat microbial resistance. Several types of nanoparticles use multiple mechanisms simultaneously to combat microbes, including nitric oxide-releasing nanoparticles (NO NPs), chitosan-containing nanoparticles (chitosan NPs), and metal-containing nanoparticles. The use of multiple simultaneous mechanisms of antimicrobial action makes the development of resistance to these nanoparticles unlikely, because multiple simultaneous gene mutations in the same microbial cell would be required for that resistance to develop [7], [5], [8], [6], [9]. It is also possible to package multiple antimicrobial agents within the same nanoparticle [10], [5]. Development of resistance to the multiple antimicrobial agents within these nanoparticles is, again, unlikely [11], possibly because it would require multiple simultaneous gene mutations in the same microbial cell. Nanoparticles can also overcome drug resistance mechanisms of microbes, including decreased uptake and increased efflux of drug from the microbial cell [10], [12], [6], biofilm formation [1], [6], and intracellular bacteria [5], [12], [6]. Finally, nanoparticles have been used to target antimicrobial agents to the site of infection, so that higher doses of drug can be given at the infected site, thereby overcoming resistance with fewer adverse effects upon the patient [13].
Section snippets
Epidemiology of antimicrobial resistance
Over the years, resistance to antimicrobial drugs has become increasingly widespread, and this has resulted in a significant threat to public health [1]. The long list of drug-resistant bacteria includes sulfonamide-resistant, penicillin-resistant, methicillin-resistant, and vancomycin-resistant Staphylococcus aureus, macrolide-resistant Streptococcus pyogenes, penicillin-resistant Streptococcus pneumoniae, vancomycin-resistant Enterococcus, multidrug-resistant Mycobacterium tuberculosis,
Development of resistance to antimicrobial drugs
Development of drug resistance occurs in (at least) three steps: Acquisition by microbes of resistance genes, followed by expression of those resistance genes, followed by selection for microbes expressing those resistance genes. First, bacteria acquire resistance to single and multiple drugs through horizontal gene transfer by transformation, conjugation, and transduction [1]. Bacteria can also acquire resistance genes by spontaneous mutation of existing genes [18]. Multiple drug resistance is
Mechanisms by which nanoparticles combat microbial resistance
There are numerous mechanisms by which nanoparticles combat microbial resistance. First, several types of nanoparticles prevent development of resistance by using multiple mechanisms simultaneously to combat microbes, including nitric oxide-releasing nanoparticles (NO NPs), chitosan-containing nanoparticles (chitosan NPs), and metal-containing nanoparticles [7], [5], [8], [6], [9]. Packaging multiple antimicrobial drugs within the same nanoparticle is another way of preventing development of
Conclusion
This review article has discussed the epidemiology of microbial resistance, mechanisms of drug resistance used by microbes, and the mechanisms used by nanoparticles to overcome this resistance. The article has described how nitric oxide-releasing nanoparticles (NO NPs), chitosan-containing nanoparticles (chitosan NPs), and metal-containing nanoparticles all use multiple mechanisms simultaneously to combat microbes, thereby making the development of resistance to these nanoparticles unlikely [7]
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This review is part of the Advanced Drug Delivery Reviews theme issue on “Nanotechnology and drug resistance”.