Log reduction of multidrug-resistant Gram-negative bacteria by the neutrophil-derived recombinant bactericidal/permeability-increasing protein

Weitz, Andrea; Spotnitz, Russell; Collins, Jennifer; Ovadia, Steven; Iovine, Nicole M.

doi:10.1016/j.ijantimicag.2013.07.019

Cited by 8 publications

(10 citation statements)

References 15 publications

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“…Finally, we were unable to complete the original trial of increasing opebacan dose and duration due to long-term disruption of drug supply. Given that rBPI 21 has concentration-dependent effects 28 , it is possible and perhaps likely that greater benefit would be observed with prolonged and/or higher dosing. These results suggest that opebacan can be safely administered to individuals undergoing myeloablative HCT.…”

Section: Discussionmentioning

confidence: 99%

“…In human trials, intravenous (IV) administration of either rBPI 23 or rBPI 21 has appeared safe and non-immunogenic 24 – 27 and ameliorated LPS-induced changes in parameters including cardiac index, cytokine release and coagulation. rBPI 21 and rBPI 23 have bactericidal activity and exhibit synergy with conventional antibiotics, including activity against antibiotic-resistant bacteria 18 , 28 .…”

Section: Introductionmentioning

confidence: 99%

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Pilot experience with opebacan/rBPI21 in myeloablative hematopoietic cell transplantation

et al. 2015

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Bacterial infection and inflammation contribute significantly to the morbidity and mortality of myeloablative allogeneic hematopoietic cell transplantation (HCT). Endotoxin, a component of the outer membrane of Gram-negative bacteria, is a potent inflammatory stimulus in humans. Bactericidal/permeability increasing protein (BPI), a constituent of human neutrophil granules, binds endotoxin thereby precluding endotoxin-induced inflammation and also has direct anti-infective properties against bacteria. As a consequence of myeloablative therapy used in preparation for hematopoietic cell infusion, patients experience gastrointestinal leak of bacteria and bacterial toxins into the systemic circulation and a period of inflammatory cytokine elevation associated with subsequent regimen-related toxicities. Patients frequently become endotoxemic and febrile as well as BPI-deficient due to sustained neutropenia. To examine whether enhancing endotoxin-neutralizing and anti-infective activity by exogenous administration of a recombinant N-terminal fragment of BPI (rBPI 21, generic name opebacan) might ameliorate regimen-related toxicities including infection, we recruited patients scheduled to undergo myeloablative HCT to participate in a proof-of-concept prospective phase I/II trial. After the HCT preparative regimen was completed, opebacan was initiated 18-36 hours prior to administration of allogeneic hematopoietic stem cells (defined as Day 0) and continued for 72 hours. The trial was to have included escalation of rBPI 21 dose and duration but was stopped prematurely due to lack of further drug availability. Therefore, to better understand the clinical course of opebacan-treated patients (n=6), we compared their outcomes with a comparable cohort meeting the same eligibility criteria and enrolled in a non-interventional myeloablative HCT observational study (n = 35). Opebacan-treated participants had earlier platelet engraftment (p=0.005), mirroring beneficial effects of rBPI 21 previously observed in irradiated mice, fewer documented infections (p=0.03) and appeared less likely to experience significant regimen-related toxicities (p=0.05). This small pilot experience supports the potential utility of rBPI 21 in ameliorating HCT-related morbidity and merits further exploration.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pilot experience with opebacan/rBPI21 in myeloablative hematopoietic cell transplantation

et al. 2015

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“…In 2013, it was reported that A. baumannii was sensitive to BPI ( 23 ). Thus, we challenged mice with A. baumannii to confirm the loss of BPI function.…”

Section: Resultsmentioning

confidence: 99%

“…Human BPI is mainly expressed in neutrophils, where it has a bactericidal function, ( 25 ) and it has also been demonstrated in neutrophil extracellular traps ( 26 ). In this study, we generated BPI global knockout mice, and challenged mice with A. baumannii , a gram-negative bacterium ( 23 ). Our results showed that the number of A. baumannii in the peritoneal, liver and spleen was increased in BPI KO mice.…”

Section: Discussionmentioning

confidence: 99%

Bactericidal Permeability Increasing Protein Deficiency Aggravates Acute Colitis in Mice by Increasing the Serum Levels of Lipopolysaccharide

Kong

Kang

et al. 2021

Front. Immunol.

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ObjectiveThe objective of this study was to understand the role of bactericidal permeability increasing protein (BPI) in the pathogenesis of experimental murine colitis.MethodsWe used the Cre-LoxP system to generate BPI knockout (BPI KO) mice. Acute colitis was induced in BPI KO mice and wild-type (WT) mice by subjecting the mice to 5% dextran sulfate sodium (DSS). Mice were observed for symptoms of experimental colitis. The survival of BPI KO mice to infection with Acinetobacter baumannii, a gram-negative bacterium, was also assessed.ResultsSouthern blot, RT-PCR, and western blot results showed that the 2nd and 3rd exons of the murine Bpi gene were knocked out systemically, confirming successful construction of the BPI KO mouse. BPI KO mice subjected to DSS showed increased symptoms of experimental colitis, increased colonic mucosal damage, increased epithelial permeability, elevated levels of serum LPS, and a disrupted fecal microbiome as compared with WT mice. Furthermore, BPI KO mice challenged intraperitoneally with A. baumannii died sooner than WT mice, and the total number of bacteria in the abdominal cavity, spleen, and liver was increased in BPI KO mice as compared to WT mice.ConclusionsWe successfully generated BPI KO mice. The BPI KO mice developed worse colitis than WT mice by increased colitis symptoms and colonic mucosal damage, elevated levels of serum LPS, and a disrupted microbiome. BPI could be a potential target for treatment of ulcerative colitis in humans.

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“…The use of rBPI‐21 against KP or E. cloacae cells in blood/plasma suggested a leukocyte‐independent activity, and therefore a direct permeabilization was proposed, although no synergy with antibiotics was seen (Levy et al ., 2000 ). A ≈ 2 log unit reduction in multidrug‐resistant PA and AB viable cells was shown in vitro after 1 h with achievable doses of rBPI‐21, although KP remained mostly resistant (Weitz et al ., 2013 ). The Asp190Ala variant of BPI5 (murine BPI fold containing family B, member 5; also known as Bpifb5 or Lplunc5) showed a significant increase in LPS‐binding capacity and in in vitro antipseudomonal power (Wu et al ., 2016 ).…”

Section: Bacterial Envelope‐targeting Mammalian Humoral Innate Immuni...mentioning

confidence: 99%

Mammals' humoral immune proteins and peptides targeting the bacterial envelope: from natural protection to therapeutic applications against multidrug‐resistant Gram‐negatives

et al. 2022

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Mammalian innate immunity employs several humoral ‘weapons’ that target the bacterial envelope. The threats posed by the multidrug‐resistant ‘ESKAPE’ Gram‐negative pathogens (Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.) are forcing researchers to explore new therapeutic options, including the use of these immune elements. Here we review bacterial envelope‐targeting (peptidoglycan and/or membrane‐targeting) proteins/peptides of the mammalian immune system that are most likely to have therapeutic applications. Firstly we discuss their general features and protective activity against ESKAPE Gram‐negatives in the host. We then gather, integrate, and discuss recent research on experimental therapeutics harnessing their bactericidal power, based on their exogenous administration and also on the discovery of bacterial and/or host targets that improve the performance of this endogenous immunity, as a novel therapeutic concept. We identify weak points and knowledge gaps in current research in this field and suggest areas for future work to obtain successful envelope‐targeting therapeutic options to tackle the challenge of antimicrobial resistance.

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Log reduction of multidrug-resistant Gram-negative bacteria by the neutrophil-derived recombinant bactericidal/permeability-increasing protein

Cited by 8 publications

References 15 publications

Pilot experience with opebacan/rBPI21 in myeloablative hematopoietic cell transplantation

Pilot experience with opebacan/rBPI21 in myeloablative hematopoietic cell transplantation

Bactericidal Permeability Increasing Protein Deficiency Aggravates Acute Colitis in Mice by Increasing the Serum Levels of Lipopolysaccharide

Mammals' humoral immune proteins and peptides targeting the bacterial envelope: from natural protection to therapeutic applications against multidrug‐resistant Gram‐negatives

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