Recent advances in the treatment of pathogenic infections using antibiotics and nano-drug delivery vehicles

Figures & data

Table 1 WHO listing (third revision, 2012)¹⁶ of critically important antimicrobials for human medicine

Critically important	Highly important	Important	Unclassified
Cephalosporins (third and fourth generation)a	Cephalosporins (first and second generation)	Nitrofurantoins	Carbadox
Fluoro and other quinolonesa	Penicillins
Glycopeptidesa	Pleuromutilins
Macrolides and ketolidesa	Streptogramins
Glycylcyclines	Riminofenazines
Aminoglycosides	Aminopenicillins	Aminocyclitols	Ionophores
Carbapenems/penems	Amphenicols	Cyclic polypeptides	Bambermycins
Cyclic esters	Lincosamides	Nitroimidazoles
Lipopeptides	Steroid antibacterials
Macrolides and ketolidesa	Streptogramins
Monobactams	Sulfonamides
Oxazolidinones	Sulfones
Penicillins (natural aminopenicillins)	Tetracyclines
Polymyxins
Rifamycins
Tuberculosis and other mycobacterial drugs

Notes:

a The top four critically important antimicrobials are prioritized based on: 1) high absolute number of people affected by diseases for which the antimicrobial is the sole or one of few alternatives to treat serious human disease, and 2) high frequency of use of the antimicrobial for any indication in human medicine, since usage may favor selection of resistance.

Figure 1 Checkerboard magnetic chip for cell capture.

Notes: (A) Checkerboard magnetic array with alternating polarity. (B) Magnetic field strength (Bz) between two checkerboard arrays. (C) Magnetic force simulation for 1 µm magnetic beads exposed to a simple two-pole system or checkerboard array. (D) Chip-array arrangement. (E) The effect of flow rate on the enrichment ratio. (F) Magnetic enrichment of hybridoma cells. Cells were labeled with CD45-specific magnetic beads; IgG2b beads were used as a control. Image reproduced with permission from Park KS, Kim H, Kim S, et al. Nanomagnetic system for rapid diagnosis of acute infection. ACS Nano. 2017;11(11):11425–11432. Copyright 2017 American Chemical Society.⁴⁷

Figure 2 NP-coating attenuates Helicobacter pylori (H. pylori) pathobiology. Gastric cancer cells were infected with NP -H. pylori^GFP complexes estimated to maximally cover approximately 25% (Si30–25%: 1 × 10⁸ bacteria, 600 µg mL⁻¹ Si30; 10 min PBS) or 0.25% (Si30–0.25%: 1 × 10⁸ bacteria, 60 µg mL⁻¹ Si30, 10 min PBS) of the bacterial surface, respectively.

Notes: (A) Fluorescent microscope image demonstrating NP inhibition of the “hummingbird” phenotype. (B) Immunoblot analysis showing NP (Si30) attenuated type IV secretion system function and decreasing phosphorylated CagA levels. (C) β-Actin normalized phosphorylated CagA levels. (D) NP concentration-dependent decrease in IL-8 secretion. Westmeier D, Posselt G, Hahlbrock A, et al. Nanoparticle binding attenuates the pathobiology of gastric cancer-associated Helicobacter pylori. Nanoscale. 2018;10(3):1453–1463. Adapted by permission of The Royal Society of Chemistry.⁹⁵ Statistical significance was determined by using the Mann-Whitney test or paired t-test assuming significance at *P=0.05.
Abbreviations: Ctrl, control; NP, nanoparticle.

Figure 3 In vivo anti-Helicobacter pylori therapeutic efficacy of AGS-NP (CLR).

Notes: (A) H. pylori infection mouse model subject to inoculation, development, and treatment protocols. (B) Analysis of bacterial loads in mice treated with PBS, free CLR, PEG-NP (CLR), or AGS-NP (CLR) (n=6 per group). Bars represent median values. *P<0.05, **P<0.01, and ***P<0.001. Image reproduced from Coating nanopar-ticles with gastric epithelial cell membrane for targeted antibiotic delivery against Helicobacter pylori infection. Advanced Therapeutics. 2018;1(2):1800016. Copyright Wiley-VCH Verlag GmbH & Co. KGaA. Reproduced with permission.¹²⁶
Abbreviations: CFU, colony-forming unit; CLR, clarithromycin; NP, nanoparticle.

Table 2 Targeted antibacterial therapies

Delivery vehicle	Antibacterial agent	Pathogen	Reference
Monoolein, DOTAP, and monoolein LLC NPs	Rifampicin	Staphylococcus aureus	^Citation74
/	SYN-004, β-lactamase enzymes	Clostridium difficile	^Citation75
/	OFBT	Gram-negative bacteria, Gram-positive bacteria, and fungi	^Citation76
/	PDMAEMA-b-PTMA, QDMA-b-PTMA	MRSA	^Citation82
/	P(CitAPDMAEMA)	Escherichia coli, S. aureus	^Citation83
Peptidomimetic polyurethanes	/	E. coli, S. aureus	^Citation84
pH-sensitive lipids	Vancomycin	MRSA	^Citation85
Solid lipid nanoparticles	Vancomycin	MRSA	^Citation88
Chitosan/TPP	Amoxicillin	Helicobacter pylori	^Citation91
PLGA/UCCs-2 NPs	Amoxicillin	H. pylori	^Citation92
Silica NPs	/	H. pylori	^Citation95
Lipase-sensitive polyurethane micelles (PUM-Ag)	Ag NPs	E. coli, S. aureus	^Citation98
Lipid and peptide-coated mesoporous silica NPs	Gentamicin	S. aureus Infected preosteoblast, macrophage	^Citation101
100-faceted Pd cubes, 111-faceted Pd octahedrons	/ /	Gram-positive bacteria Gram-negative bacteria	^Citation117
Amoxicillin-coated AuNPs	Complexed with gold	S. aureus	^Citation120
AGS-NPs	Clarithromycin	H. pylori	^Citation126
PpZEV NPs	Vancomycin	MRSA	^Citation129

Abbreviations: AGS, gastric epithelial cells; DOTAP, N-[1-(2,3-Dioleoyloxy)propyl]-N,N,N-trimethylammonium methyl sulfate; LLC, lyotropic liquid crystalline; NP, nanoparticle; OFBT, oligo-(7,7′-bifluoren-benzo[c][1,2,5]thiadiazole); pCitAPDMAEMA, poly(N′-citraconyl-2-(3-aminopropyl-N,N-dimethylammonium)ethyl methacrylate); PDMAEMA, poly(N,N-dimethylaminoethyl methacrylate); PLGA/UCC, poly (lactide-co glycolide/ureido-conjugated chitosan; PpZEV, PEG-PLGA and Eudragit E100, and chitosan; PUM, polyurethane micelles; QDMA, quaternary dimethylamino; TPP, tripolyphosphate.

Figure 4 Structure of hNS.

Notes: (A) Schematic diagram depicting hNS and its mechanism of neutralizing PFTs. (B) Nanoparticle hydrodynamic size (diameter) and zeta potential (mV) (n=3) before and after membrane coating. (C) Transmission electron microscopy image of hNS. (D) Diameter stability of hNS over 5 days in different media (n=3). Image modified with permission from Chen Y, Chen M, Zhang Y, et al. Broad-spectrum neutralization of pore-forming toxins with human erythrocyte membrane-coated nanosponges. Adv Healthc Mater. 2018;7(13):e1701366. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.¹⁵⁵
Abbreviations: hNS, human RBC nanosponge; PFTs, pore-forming toxins; PLGA, poly (lactide-co-glycolide); RBC, red blood cell.

Figure 5 CFU assay.

Note: Image reproduced from Jamil et al¹⁸¹ with permission (Copyright 2016 Frontier Publishing).
Abbreviations: CFU, colony-forming unit; CSNP, chitosan nanoparticles; E. coli, Escherichia coli; KP, Klebsiella pneumoniae; MRSA, methicillin-resistant Staphylococcus aureus; NAB, nano-antibiotic; Pseudo, Pseudomonas aeruginosa.

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