This journal is © The Royal Society of Chemistry 2014 Chem. Soc. Rev. Cite this: DOI: 10.1039/c3cs60218d Nanosilver-based antibacterial drugs and devices: Mechanisms, methodological drawbacks, and guidelines Loris Rizzello and Pier Paolo Pompa* Despite the current advancement in drug discovery and pharmaceutical biotechnology, infection diseases induced by bacteria continue to be one of the greatest health problems worldwide, afflicting millions of people annually. Almost all microorganisms have, in fact, an intrinsic outstanding ability to flout many therapeutic interventions, thanks to their fast and easy-to-occur evolutionary genetic mechanisms. At the same time, big pharmaceutical companies are losing interest in new antibiotics development, shifting their capital investments in much more profitable research and development fields. New smart solutions are, thus, required to overcome such concerns, and should combine the feasibility of industrial production processes with cheapness and effectiveness. In this framework, nanotechnology-based solutions, and in particular silver nanoparticles (AgNPs), have recently emerged as promising candidates in the market as new antibacterial agents. AgNPs display, in fact, enhanced broad-range antibacterial/antiviral properties, and their synthesis procedures are quite cost effective. However, despite their increasing impact on the market, many relevant issues are still open. These include the molecular mechanisms governing the AgNPs–bacteria interactions, the physico-chemical parameters underlying their toxicity to prokaryotes, the lack of standardized methods and materials, and the uncertainty in the definition of general strategies to develop smart antibacterial drugs and devices based on nanosilver. In this review, we analyze the experimental data on the bactericidal effects of AgNPs, discussing the complex scenario and presenting the potential drawbacks and limitations in the techniques and methods employed. Moreover, after analyzing in depth the main mechanisms involved, we provide some general strategies/procedures to perform antibacterial tests of AgNPs, and propose some general guidelines for the design of antibacterial nanosystems and devices based on silver/nanosilver. Introduction The evolutionary mechanisms of humans and their symbiotic bacteria have been shared for thousands of years, resulting in the selection of interactions in the form of mutualism and/or commensalism. 1–5 When such symbiosis turns out to a parasitic relationship, typically due to ecological or genetic/physiological changes, infections may occur within the host organisms. In this framework, bacteria were recognized to be the cause of several human diseases since the late 1800s; starting from that period, significant efforts have been pursued on many fronts to achieve solutions to this serious concern, including vaccination, improvement of hygienic conditions, and anti- biotics development. Since their discovery, antimicrobial drugs have, in particular, saved millions of people and eased several patients suffering from chronic infections. Table 1 summarizes the history and chronological steps of the approval of some important antibacterial compounds by the Food and Drug Administration (representative data from 1935 to 2004). 6 Albeit in the past the medical community optimistically dubbed antimicrobial agents as ‘‘the miracle drugs’’, subsequent evidences highlighted their strong limitations. 7–11 It should be, in fact, mentioned that, over time, bacteria evolved several resistance mechanisms against antibiotics, thus making their infection treatment extremely difficult. 12–15 As an example, penicillin was introduced in the early 1940s for the extensive treatment of Staphylococcus aureus related infections, and the first penicillin resistant S. aureus strains were identified in 1942. Fig. 1 shows the timescale evolution of the approval of some important antibiotics, along with the evidences of the rise of bacterial resistance. It is clear that, upon commercialization of a new compound, resistance is observed even a few years later (typically, between 1 and 3 years). 16–18 Istituto Italiano di Tecnologia (IIT), Center for Bio-Molecular Nanotechnologies@UniLe, Via Barsanti, 73010 Arnesano (Lecce), Italy. E-mail: pierpaolo.pompa@iit.it; Fax: +39-0832-1816230; Tel: +39-0832-1816214 Received 28th June 2013 DOI: 10.1039/c3cs60218d www.rsc.org/csr Chem Soc Rev REVIEW ARTICLE Published on 02 December 2013. Downloaded by University College London on 02/12/2013 14:35:09. View Article Online View Journal