Sublethal Levels of Antibiotics Promote Bacterial Persistence in Epithelial Cells

Liu, Xiaoye; Liu, Fei; Ding, Shuangyang; Shen, Jianzhong; Zhu, Kui

doi:10.1002/advs.201900840

Cited by 45 publications

(40 citation statements)

References 77 publications

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“…[ 31 ] These findings indicate the activation of autophagy in IEC‐6 cells infected with S. aureus , agreeing with previous reports that bacteria can persist in the cytoplasm of mammalian cells by hijacking autophagy. [ 32,33 ] In addition, S. aureus escaped the degradation by lysosome, indicating the inhibition of lysosomal acidification (Figure S18E, Supporting Information). Together, these results suggest that S. aureus survival and replicate in host cells through hijacking autophagy.…”

Section: Resultsmentioning

confidence: 99%

Efficient Killing of Multidrug‐Resistant Internalized Bacteria by AIEgens In Vivo

Liu

Zhang

et al. 2021

Advanced Science

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Bacteria infected cells acting as “Trojan horses” not only protect bacteria from antibiotic therapies and immune clearance, but also increase the dissemination of pathogens from the initial sites of infection. Antibiotics are hard and insufficient to treat such hidden internalized bacteria, especially multidrug‐resistant (MDR) bacteria. Herein, aggregation‐induced emission luminogens (AIEgens) such as N,N‐diphenyl‐4‐(7‐(pyridin‐4‐yl) benzo [c] [1,2,5] thiadiazol‐4‐yl) aniline functionalized with 1‐bromoethane (TBP‐1) and (3‐bromopropyl) trimethylammonium bromide (TBP‐2) (TBPs) show potent broad‐spectrum bactericidal activity against both extracellular and internalized Gram‐positive pathogens. TBPs trigger reactive oxygen species (ROS)‐mediated membrane damage to kill bacteria, regardless of light irradiation. TBPs effectively kill bacteria without the development of resistance. Additionally, such AIEgens activate mitochondria dependent autophagy to eliminate internalized bacteria in host cells. Compared to the routinely used vancomycin in clinic, TBPs demonstrate comparable efficacy against methicillin‐resistant Staphylococcus aureus (MRSA) in vivo. The studies suggest that AIEgens are promising new agents for the treatment of MDR bacteria associated infections.

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Section: Resultsmentioning

confidence: 99%

Efficient Killing of Multidrug‐Resistant Internalized Bacteria by AIEgens In Vivo

Liu

Zhang

et al. 2021

Advanced Science

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“…9,12 This moderate invasion characteristic of low-virulence isolates might be related to long-term persistence because epithelial cells can provide special niches for various bacteria to tolerate multiple antibiotics. 30 The survival of intracellular CRKP might serve as a reservoir in the host, resulting in colonization, recurrence of infections, and relapses after antibiotic therapy.…”

Section: Discussionmentioning

confidence: 99%

Genomic and Phenotypic Analysis of Persistent Carbapenem-Resistant Klebsiella pneumoniae Isolates from a 5-Year Hospitalized Patient

Yang

Sun

Chen

et al. 2021

Microbial Drug Resistance

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The emerging epidemic of carbapenem-resistant Klebsiella pneumoniae (CRKP) is a global public health crisis. However, the phylogenetic affiliation and pathotypic status of CRKP strains in the host colonization period under consistent antibiotic treatments are not well characterized. In this study, a 5-year tracking study was performed, in which a patient admitted to an intensive care unit was recruited and then screened for the carriage of CRKP based on microbiological culture. Nine isolates from the sputum or stool samples were acquired and subjected to real-time whole-genome sequencing, antimicrobial susceptibility testing, Galleria mellonella larval infection, and epithelial cell invasion assay. All nine isolates showed phenotypic resistance to carbapenems, quinolones, and aminoglycosides. Altogether, bla KPC-2 and 10 other antibiotic resistance genes were identified and all nine CRKP isolates exhibited low virulence with more than 38 virulence factors. All but one variant belonged to ST11 with a novel sequence type, differing at the phoE locus. The isolates shared the same plasmid replicon type, prophages, and capsular serotype (K47) with few single-nucleotide polymorphism variations, consistent with epidemiological clones. Furthermore, these CRKP isolates displayed the ability of moderate invasion of lung epithelial cells. Meanwhile, a deficiency of chromosomal type IV secretion system-related gene cluster was detected after 2 years of carriage. Our findings demonstrated that low-virulence CRKP clones could colonize in the gut and respiratory tract under multiple antibiotic stresses, suggesting the strong colonization adaptability of CRKP to the host. Ethical approval was given by The Second

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“…paragallinarum in epithelial cells and macrophages based on confocal microscopy analysis and gentamycin protection assays ( S14A and S14B Fig ), consistent with previous studies showing that Haemophilus spp. and other bacteria can also initiate intracellular survival [ 40 – 42 ]. Hence, we deduce that S .…”

Section: Resultsmentioning

confidence: 99%

Resident bacteria contribute to opportunistic infections of the respiratory tract

Wang

Yang

et al. 2021

PLoS Pathog

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Opportunistic pathogens frequently cause volatile infections in hosts with compromised immune systems or a disrupted normal microbiota. The commensalism of diverse microorganisms contributes to colonization resistance, which prevents the expansion of opportunistic pathogens. Following microbiota disruption, pathogens promptly adapt to altered niches and obtain growth advantages. Nevertheless, whether and how resident bacteria modulate the growth dynamics of invasive pathogens and the eventual outcome of such infections are still unclear. Here, we utilized birds as a model animal and observed a resident bacterium exacerbating the invasion of Avibacterium paragallinarum (previously Haemophilus paragallinarum) in the respiratory tract. We first found that negligibly abundant Staphylococcus chromogenes, rather than Staphylococcus aureus, played a dominant role in Av. paragallinarum-associated infectious coryza in poultry based on epidemic investigations and in vitro analyses. Furthermore, we determined that S. chromogenes not only directly provides the necessary nutrition factor nicotinamide adenine dinucleotide (NAD+) but also accelerates its biosynthesis and release from host cells to promote the survival and growth of Av. paragallinarum. Last, we successfully intervened in Av. paragallinarum-associated infections in animal models using antibiotics that specifically target S. chromogenes. Our findings show that opportunistic pathogens can hijack commensal bacteria to initiate infection and expansion and suggest a new paradigm to ameliorate opportunistic infections by modulating the dynamics of resident bacteria.

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Sublethal Levels of Antibiotics Promote Bacterial Persistence in Epithelial Cells

Cited by 45 publications

References 77 publications

Efficient Killing of Multidrug‐Resistant Internalized Bacteria by AIEgens In Vivo

Efficient Killing of Multidrug‐Resistant Internalized Bacteria by AIEgens In Vivo

Genomic and Phenotypic Analysis of Persistent Carbapenem-Resistant Klebsiella pneumoniae Isolates from a 5-Year Hospitalized Patient

Resident bacteria contribute to opportunistic infections of the respiratory tract

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