Nanotargeting of Resistant Infections with a Special Emphasis on the Biofilm Landscape

Abstract

Bacterial resistance to antimicrobial compounds is a growing concern in medical and public health circles. Overcoming the adaptable and duplicative resistance mechanisms of bacteria requires chemistry-based approaches. Engineered nanoparticles (NPs) now offer unique advantages toward this effort. However, most in situ infections (in humans) occur as attached biofilms enveloped in a protective surrounding matrix of extracellular polymers, where survival of microbial cells is enhanced. This presents special considerations in the design and deployment of antimicrobials. Here, we review recent efforts to combat resistant bacterial strains using NPs and, then, explore how NP surfaces may be specifically engineered to enhance the potency and delivery of antimicrobial compounds. Special NP-engineering challenges in the design of NPs must be overcome to penetrate the inherent protective barriers of the biofilm and to successfully deliver antimicrobials to bacterial cells. Future challenges are discussed in the development of new antibiotics and their mechanisms of action and targeted delivery via NPs.

Figure 1.

Nanoparticle-based design strategies for intracellular delivery applications [Reprinted with permission from ref . Copyright 2011 Royal Society of Chemistry].

Figure 2.

Schematic representation illustrating the antimicrobial mechanisms that have been demonstrated for various metal-based NPs [Reprinted with permission from ref . Copyright 2019 Shaikh et al.].

Figure 3.

Antimicrobial drug resistance mechanisms in bacteria. (1) Prevention of antimicrobial drug penetration into the bacterial cell by bacterial cell envelope. (2) Removal of antimicrobial drug from bacterial cell by nonspecific efflux pumps. (3) Acquisition of new genetic material from drug resistant bacterial strain. (4) Inactivation of antimicrobial drug by intracellular modification [Reprinted with permission from ref . Copyright 2018 Elsevier].

Figure 4.

Protective attributes of biofilms. Bacteria within biofilms secrete a wide range of extracellular polymeric substances, collectively called EPS, which secure attachment, slow the diffusion of antimicrobials such as antibiotics and NPs, and protect bacterial cells from external stressors. Within a biofilm, there is enhanced gene exchange (e.g., AR genes) and secretion of extracellular enzymes such as β-lactamases, that can degrade antibiotics. Together, these attributes enhance resistance of biofilm infections to antibiotics and other antimicrobial approaches.

Figure 5.

Control of NP entry into biofilms. Small-scale changes in the relative density of EPS influences the penetration of NPs (red) into a biofilm. (A) Water-filled pore spaces (i.e., white spaces) in EPS (gray) are interconnected through which NPs diffuse into the matrix. It is hypothesized that (A) when EPS pore spacing is large NPs more easily penetrate the matrix. (B) However, when EPS are densely packed, pore spaces between adjacent polymers on average are small and limit their diffusivity. Therefore, only small diameter NPs (e.g., 10–30 nm dia), may penetrate to reach bacterial cells. The design of NPs with specific hydrated coatings (i.e., coronas) or surface properties may enhance their diffusion through EPS to reach infectious bacterial cells in a biofilm. NPs indicated “A” and “B” represent NPs with small diameters with different functional groups attached.

Figure 6.

Targeting quorum sensing. Schematic of QS in bacteria as well as methods to block this signaling mechanism. AHL dependent QS within biofilms (left) can be blocked using competitive QS inhibition that outcompetes AHL for AHL receptors (middle) or quorum quenching enzymes that inactivate AHL signals (right) [Reprinted from ref . Copyright 2018 Beitelshees et al.].

Figure 7.

Quorum quenching potential of nanomaterials. The agents interrupt QS signaling in different ways: (a) suppressing the production of autoinducers via reduction the activity of LuxI-type cognate receptor synthase and ATP binding cassettes, which produces AHLs and oligopeptides respectively; (b) degrading the autoinducers; (c) inhibiting the binding of autoinducers to the LuxR-type receptor protein; and (d) inhibiting biofilm formation [Reprinted with permission from ref . Copyright 2017 Taylor & Francis].