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Review
. 2017 Jul;174(14):2225-2236.
doi: 10.1111/bph.13664. Epub 2016 Dec 7.

Targeting the hard to reach: challenges and novel strategies in the treatment of intracellular bacterial infections

Affiliations
Review

Targeting the hard to reach: challenges and novel strategies in the treatment of intracellular bacterial infections

Nor Fadhilah Kamaruzzaman et al. Br J Pharmacol. 2017 Jul.

Abstract

Infectious diseases continue to threaten human and animal health and welfare globally, impacting millions of lives and causing substantial economic loss. The use of antibacterials has been only partially successful in reducing disease impact. Bacterial cells are inherently resilient, and the therapy challenge is increased by the development of antibacterial resistance, the formation of biofilms and the ability of certain clinically important pathogens to invade and localize within host cells. Invasion into host cells provides protection from both antibacterials and the host immune system. Poor delivery of antibacterials into host cells causes inadequate bacterial clearance, resulting in chronic and unresolved infections. In this review, we discuss the challenges associated with existing antibacterial therapies with a focus on intracellular pathogens. We consider the requirements for successful treatment of intracellular infections and novel platforms currently under development. Finally, we discuss novel strategies to improve drug penetration into host cells. As an example, we discuss our recent demonstration that the cell penetrating cationic polymer polyhexamethylene biguanide has antibacterial activity against intracellular Staphylococcus aureus.

Linked articles: This article is part of a themed section on Drug Metabolism and Antibiotic Resistance in Micro-organisms. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.14/issuetoc.

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Figures

Figure 1
Figure 1
Illustration of bacterial localization inside the host cells and cellular barriers to antibacterial access intracellular targets. Following host cell entry, bacteria are typically enclosed inside endosomes. Bacteria can continue to survive and replicate inside endosomes as they mature into phagosomes or phagolysosomes. Certain bacteria can also induce endosome rupture and enter the cytosol. Red arrows depict three major barriers that limit antibacterial access to intracellular bacteria: (1) the plasma membrane of host cells, (2) the phagosomal/phagolysosomal membrane and (3) the bacterial cell wall. For a more detailed description of the composition of the mammalian and bacterial plasma membranes, see Silhavy et al. (2010), Marquardt et al. (2015) and Simons and Sampaio (2016).
Figure 2
Figure 2
The structure of PHMB. PHMB is a cationic polymer of repeating hexamethylene biguanide groups, with n average = 10–12 (n is the number of structural unit repeats) and MW 3025 g·mol−1. Reprinted from Kamaruzzaman et al., 2016.
Figure 3
Figure 3
Intracellular localization and bactericidal activities of nadifloxacin and PHMB against intracellular MRSA. (A) Colocalization of PHMB‐FITC with epidemic methicillin‐resistant S. aureus (EMRSA)‐15 in keratinocytes. Keratinocytes were infected with EMRSA‐15 followed by treatment with PHMB‐FITC (green). Keratinocytes were labelled with DAPI (blue) for keratinocytes and EMRSA‐15 nuclei staining and wheat germ agglutination (WGA) (red) for keratinocyte membrane stain. Upper panels are images of infected cells and merged images. Lower panels are enlarged images that clearly show colocalization between PHMB‐FITC (green) and EMRSA‐15 (blue). White scale bar is 25 μm. (B) Survival of EMRSA‐15 within keratinocytes after treatment with nadifloxacin and PHMB. Keratinocytes infected with strains of EMRSA‐15 were either untreated or treated with increasing concentrations of nadifloxacin or PHMB. Untreated cultures were used to establish colony forming unit values corresponding to 100% survival. Reprinted from Kamaruzzaman et al., 2016.

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