Flourishing Antibacterial Strategies for Osteomyelitis Therapy

Abstract

Osteomyelitis is a destructive disease of bone tissue caused by infection with pathogenic microorganisms. Because of the complex and long-term abnormal conditions, osteomyelitis is one of the refractory diseases in orthopedics. Currently, anti-infective therapy is the primary modality for osteomyelitis therapy in addition to thorough surgical debridement. However, bacterial resistance has gradually reduced the benefits of traditional antibiotics, and the development of advanced antibacterial agents has received growing attention. This review introduces the main targets of antibacterial agents for treating osteomyelitis, including bacterial cell wall, cell membrane, intracellular macromolecules, and bacterial energy metabolism, focuses on their mechanisms, and predicts prospects for clinical applications.

Keywords: antibacterial agent; antibacterial mechanism; biomaterial; osteomyelitis therapy; targeted antibacterial strategy.

Scheme 1

Antibacterial treatment strategies for osteomyelitis.

Figure 1

Antibacterial mechanism and effect of VAN. A) Mode of action of VAN in S. aureus. Reproduced with permission.^{[ 26 ]} Copyright 2016, Frontiers Media SA. B) Bacterial morphology of S. aureus after 24 h of co‐incubation with different groups of samples. C) Number of colony forming units and bacterial viability of S. aureus after 1 day, 7 days, and 14 days of co‐incubation with different groups of samples. Data are shown as mean ± SD (n = 3; *P < 0.05). Reproduced with permission.^{[ 30 ]} Copyright 2021, Elsevier. CFU, colony forming unit; HA, hydroxyapatite; OD, optical density; Si, silicon; VAN, vancomycin.

Figure 2

Antibacterial mechanism and effect of ROS generated by photocatalytic reaction. A) Schematic illustration of photocatalytic sterilization and osteogenesis of TiO₂/GDY. B) SEM images of MRSA after photocatalytic treatment of TiO₂/GDY nanofiber. In the magnified SEM image, the depressions (yellow arrows) formed after ROS‐induced cell wall perforation can be observed. C) Quantitative analysis of bacterial colonies infecting femurs by UV irradiation with TiO₂, TiO₂/GDY, and PBS as controls. Data are shown as mean ± SD (n = 3; ***P   <   0.001). D) H&E staining of infected femurs of mice. The orange dashed line indicates the infected area, and between the orange and blue dashed lines is the area of new bone formation. Reproduced with permission.^{[ 43 ]} Copyright 2020, Springer Nature. CFU, colony forming unit; GDY, graphdiyne; MRSA, methicillin‐resistant S. aureus; PBS, phosphate buffered saline; ROS, reactive oxygen species; TiO₂, titanium dioxide; UV, ultraviolet.

Figure 3

Antibacterial mechanism and effect of antibacterial peptides. A) Membrane dissolution mechanism models of antibacterial peptides of annular pore model, stick model, and carpet model. Reproduced with permission.^{[ 90c ]} Copyright 2017, American Society for Microbiology. B) SEM images of E. coli and MRSA after 2.5 h of co‐incubation with bare TPU and TPU‐P surfaces. C,D) Changes in electrical conductivity of E. coli and MRSA on different surfaces. E) Effects of different surfaces on permeability of E. coli cytoplasmic membrane. Reproduced with permission.^{[ 94 ]} Copyright 2021, Elsevier. Au, gold; Au‐P, peptide polymer modified gold surface; NPN, 1‐N‐phenyl‐naphthylamine; TPU, thermoplastic polyurethane; TPU‐P, peptide polymer‐modified thermoplastic polyurethane.

Figure 4

Synergistic antibacterial mechanism and effect of Ag₃PO₄/GO coating. A) Ag₃PO₄/GO coating destroyed bacterial cell membrane, protein damage, and DNA synergistically with the released Ag⁺ and its generated ROS. B) TEM image and corresponding EDS pattern of bacteria after Ag₃PO₄/GO was incubated with E. coli bacteria and irradiated with visible light at 660 nm for 10 min. C–E) Bacterial membrane damage histogram, protein concentration histogram, and DNA integrity rate histogram of bacteria after different materials were incubated with S. aureus and irradiated with 660 nm visible light for 15 min. Data are shown as mean ± SD (n = 3; *P < 0.05, **P < 0.01, ***P < 0.001). Reproduced with permission.^{[ 136 ]} Copyright 2018, American Chemical Society. GO, graphene oxide; PDA, polydopamine; Ti, titanium.

Figure 5

Antibacterial mechanism and effect of VO₂ films. A) Antibacterial mechanism of conductive VO₂ films of metallic phase. B) SEM images of VO₂ films and W‐doped VO₂ films. C) Representative photographs of re‐cultured bacterial colonies in the material and surrounding soft tissue. D,E) Corresponding quantification of live bacteria in material and surrounding soft tissue. Data are shown as mean ±  SD (n = 10; ***P < 0.001). Reproduced with permission.^{[ 144 ]} Copyright 2019, Elsevier. ADP, adenosine diphosphate; ATP, adenosine triphosphate; CFU, colony forming units; NADH, nicotinamide adenine dinucleotide; VO₂, vanadium dioxide; W, tungsten.

Figure 6

Synergistic antibacterial mechanism and effect of FEL combined with GEN. A) Schematic illustration of antibacterial mechanism of FEL combined with GEN. B) Spectrophotometers monitored fluorescence intensity to assess bacterial cell membrane permeability. Data are shown as mean ± S.D (n = 3; NS, no significance; ***P < 0.001). C) Assessment of cell membrane fluidity in MRSA by Laurdan generalized polarization. Data are shown as mean ±  S.D (n = 3; *P < 0.05, ***P < 0.001). D) GEN uptake was measured by flow cytometry after incubation with 1 MIC FEL, 1/8 MIC FEL+1/8 MIC GEN. E) PRM examined the expression levels of proteins related to energy metabolism, bacterial resistance, and biofilm formation. F) Detection of energy metabolites associated with the TCA cycle of MRSA after 8 h of incubation with FEL. Data are shown as mean ±  S.D (n = 6; **P < 0.01, ****P < 0.0001). Reproduced with permission.^{[ 153 ]} Copyright 2022, Elsevier. aacA‐aphD, aminoglycoside resistance protein; B.A, benzyl alcohol; ClpP, caseinolytic protease P; FEL, felodipine; GEN, gentamicin; GMP, guanosine monophosphate; Laurdan GP, Laurdan generalized polarization; MIC, minimal inhibitory concentrations; TCA, tricarboxylic acid.