Phage Therapy as a Promising New Treatment for Lung Infection Caused by Carbapenem-Resistant Acinetobacter baumannii in Mice

Hua, Yingqi; Luo, Tingting; Yang, Yiqi; Dong, Dong; Wang, Rui; Wang, Yanjun; Xu, Mengsha; Guo, Xia; Hu, Fupin; He, Ping

doi:10.3389/fmicb.2017.02659

Cited by 112 publications

(78 citation statements)

References 51 publications

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“…In this study, we treated bacterial pneumonia by intranasal glyphosate delivery to mice, permitting high enough concentrations in the infected site to contain resistant mutants. Intranasal administration of therapies against lung infection models has been effective due to the high drug concentration achieved by direct administration to the lung (53,54). However, this is not predictive of the ability to treat using systemic delivery, and therefore it remains uncertain whether glyphosate would be an effective inhibitor in a systemic infection such as K. pneumoniae bacteremia.…”

Section: Discussionmentioning

confidence: 99%

Amino Acid Biosynthetic Pathways Are Required for Klebsiella pneumoniae Growth in Immunocompromised Lungs and Are Druggable Targets during Infection

Silver

Paczosa

McCabe

et al. 2019

Antimicrob Agents Chemother

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The emergence of multidrug-resistant Klebsiella pneumoniae has rendered a large array of infections difficult to treat. In a high-throughput genetic screen of factors required for K. pneumoniae survival in the lung, amino acid biosynthesis genes were critical for infection in both immunosuppressed and wild-type (WT) mice. The limited pool of amino acids in the lung did not change during infection and was insufficient for K. pneumoniae to overcome attenuating mutations in aroA, hisA, leuA, leuB, serA, serB, trpE, and tyrA in WT and immunosuppressed mice. Deletion of aroA, which encodes 5-enolpyruvylshikimate-3-phosphate (EPSP) synthase class I, resulted in the most severe attenuation. Treatment with the EPSP synthase-specific competitive inhibitor glyphosate decreased K. pneumoniae growth in the lungs. K. pneumoniae expressing two previously identified glyphosate-resistant mutations in EPSP synthase had significant colonization defects in lung infection. Selection and characterization of six spontaneously glyphosate-resistant mutants in K. pneumoniae yielded no mutations in aroA. Strikingly, glyphosate treatment of mice lowered the bacterial burden of two of three spontaneous glyphosate-resistant mutants and further lowered the burden of the less-attenuated EPSP synthase catalytic mutant. Of 39 clinical isolate strains, 9 were resistant to glyphosate at levels comparable to those of selected resistant strains, and none appeared to be more highly resistant. These findings demonstrate amino acid biosynthetic pathways essential for K. pneumoniae infection are promising novel therapeutic targets.

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Section: Discussionmentioning

confidence: 99%

Amino Acid Biosynthetic Pathways Are Required for Klebsiella pneumoniae Growth in Immunocompromised Lungs and Are Druggable Targets during Infection

Silver

Paczosa

McCabe

et al. 2019

Antimicrob Agents Chemother

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“…Phages were discovered a century ago (112), although the first phages specific to MDR A. baumannii and CRAB were only characterized in 2010 and 2012 (113,114). CRAB infections have been treated with phages successfully in animals (115)(116)(117)(118)(119)(120)(121). Data from human infections remain scarce.…”

Section: New Therapeutic Optionsmentioning

confidence: 99%

New Treatment Options against Carbapenem-Resistant Acinetobacter baumannii Infections

Isler¹,

Doi

Bonomo

et al. 2019

Antimicrob Agents Chemother

240

174

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Carbapenem-resistantAcinetobacter baumannii(CRAB) is a perilous nosocomial pathogen causing substantial morbidity and mortality. Current treatment options for CRAB are limited and suffer from pharmacokinetic limitations, such as high toxicity and low plasma levels. As a result, CRAB is declared as the top priority pathogen by the World Health Organization for the investment in new drugs. This urgent need for new therapies, in combination with faster FDA approval process, accelerated new drug development and placed several drug candidates in the pipeline. This article reviews available information about the new drugs and other therapeutic options focusing on agents in clinical or late-stage preclinical studies for the treatment of CRAB, and it evaluates their expected benefits and potential shortcomings.

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“…MDR isolates of A. baumannii, including CRAB, can be targets for such bacteriophages, so they are being considered as a useful alternative to face drug resistance. No deleterious side effects associated with their use have been reported [147,148]. Phage Bϕ-C62 has shown the strongest lytic activity [147].…”

Section: Bacteriophages Endolysin (Artilysin)mentioning

confidence: 99%

Acinetobacter baumannii Resistance: A Real Challenge for Clinicians

et al. 2020

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Acinetobacter baumannii (named in honor of the American bacteriologists Paul and Linda Baumann) is a Gram-negative, multidrug-resistant (MDR) pathogen that causes nosocomial infections, especially in intensive care units (ICUs) and immunocompromised patients with central venous catheters. A. baumannii has developed a broad spectrum of antimicrobial resistance, associated with a higher mortality rate among infected patients compared with other non-baumannii species. In terms of clinical impact, resistant strains are associated with increases in both in-hospital length of stay and mortality. A. baumannii can cause a variety of infections; most involve the respiratory tract, especially ventilator-associated pneumonia, but bacteremia and skin wound infections have also been reported, the latter of which has been prominently observed in the context of war-related trauma. Cases of meningitis associated with A. baumannii have been documented. The most common risk factor for the acquisition of MDR A baumannii is previous antibiotic use, following by mechanical ventilation, length of ICU/hospital stay, severity of illness, and use of medical devices. Current efforts focus on addressing all the antimicrobial resistance mechanisms described in A. baumannii, with the objective of identifying the most promising therapeutic scheme. Bacteriophage- and artilysin-based therapeutic approaches have been described as effective, but further research into their clinical use is required

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Phage Therapy as a Promising New Treatment for Lung Infection Caused by Carbapenem-Resistant Acinetobacter baumannii in Mice

Cited by 112 publications

References 51 publications

Amino Acid Biosynthetic Pathways Are Required for Klebsiella pneumoniae Growth in Immunocompromised Lungs and Are Druggable Targets during Infection

Amino Acid Biosynthetic Pathways Are Required for Klebsiella pneumoniae Growth in Immunocompromised Lungs and Are Druggable Targets during Infection

New Treatment Options against Carbapenem-Resistant Acinetobacter baumannii Infections

Acinetobacter baumannii Resistance: A Real Challenge for Clinicians

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