A Novel Method of Serum Resistance by Escherichia coli That Causes Urosepsis

Coggon, Carrie F.; Jiang, Andrew; Goh, Kelvin G. K.; Henderson, Ian R.; Schembri, Mark A.; Wells, Timothy J.

doi:10.1128/mbio.00920-18

Cited by 32 publications

(21 citation statements)

References 16 publications

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“…In addition, we investigated effect of O-antigen on the glycine-mediated killing, which is critical for LPS-mediated serum resistance in E. coli 10,19,20 . Among the 30 clinical E. coli strains, 27 strains were O-antigen positive (Supplementary Table 3).…”

Section: Resultsmentioning

confidence: 99%

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Glycine, serine and threonine metabolism confounds efficacy of complement-mediated killing

et al. 2019

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Serum resistance is a poorly understood but common trait of some difficult-to-treat pathogenic strains of bacteria. Here, we report that glycine, serine and threonine catabolic pathway is down-regulated in serum-resistant Escherichia coli , whereas exogenous glycine reverts the serum resistance and effectively potentiates serum to eliminate clinically-relevant bacterial pathogens in vitro and in vivo. We find that exogenous glycine increases the formation of membrane attack complex on bacterial membrane through two previously unrecognized regulations: 1) glycine negatively and positively regulates metabolic flux to purine biosynthesis and Krebs cycle, respectively. 2) α-Ketoglutarate inhibits adenosine triphosphate synthase, which in together promote the formation of cAMP/CRP regulon to increase the expression of complement-binding proteins HtrE, NfrA, and YhcD. The results could lead to effective strategies for managing the infection with serum-resistant bacteria, an especially valuable approach for treating individuals with weak acquired immunity but a normal complement system.

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Section: Resultsmentioning

confidence: 99%

“…LPS is necessary for the survival of E. coli in the blood 18 . Immunoglobulin G to LPS confers serum resistance through shielding the bacteria from other antibodies that can induce complement-mediated killing 10,19,20 . The presence of capsular polysaccharide is correlated with serum resistance in bacteria 11 .…”

Section: Introductionmentioning

confidence: 99%

Glycine, serine and threonine metabolism confounds efficacy of complement-mediated killing

et al. 2019

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“…The majority of isolates screened in this study were resistant to complement, even in the presence of the KM467, and a significant proportion of the remaining susceptible isolates were protected from complement killing in the presence of increased KM467 concentrations. Antibody-mediated protection from complement has been observed previously 35 – 37 and is a major concern when it comes to antibody therapy. This observation needs to be considered when targeting bacterial O-antigens by therapeutic mAbs.…”

Section: Discussionmentioning

confidence: 99%

A novel therapeutic antibody screening method using bacterial high-content imaging reveals functional antibody binding phenotypes of Escherichia coli ST131

Maes

Dyson

Smith

et al. 2020

Sci Rep

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the increase of antimicrobial resistance (AMR), and lack of new classes of licensed antimicrobials, have made alternative treatment options for AMR pathogens increasingly attractive. Recent studies have demonstrated anti-bacterial efficacy of a humanised monoclonal antibody (mAb) targeting the O25b O-antigen of Escherichia coli ST131. To evaluate the phenotypic effects of antibody binding to diverse clinical E. coli ST131 O25b bacterial isolates in high-throughput, we designed a novel mAb screening method using high-content imaging (HCI) and image-based morphological profiling to screen a mAb targeting the O25b O-antigen. Screening the antibody against a panel of 86 clinical E. coli ST131 O25:H4 isolates revealed 4 binding phenotypes: no binding (18.60%), weak binding (4.65%), strong binding (69.77%) and strong agglutinating binding (6.98%). Impaired antibody binding could be explained by the presence of insertion sequences or mutations in o-antigen or lipopolysaccharide core biosynthesis genes, affecting the amount, structure or chain length of the o-antigen. the agglutinating binding phenotype was linked with lower o-antigen density, enhanced antibody-mediated phagocytosis and increased serum susceptibly. this study highlights the need to screen candidate mAbs against large panels of clinically relevant isolates, and that Hci can be used to evaluate mAb binding affinity and potential functional efficacy against AMR bacteria. Antimicrobial resistance (AMR) is one of the greatest current challenges in global health 1. Increasing AMR and a lack of antimicrobials in the pharmaceutical pipeline makes alternative therapeutic approaches increasingly important. Passive antibody transfer has historically been used to treat bacterial infections, such as diphtheria, tetanus, and pneumococcal pneumonia 2,3 , making antibodies a potential therapeutic approach. Many biologics, including monoclonal antibodies (mAbs) are being used increasingly in oncology, autoimmune diseases, and the prevention of some viral infections 4,5. However, mAbs have been found to have limited utility against bacteria 6. This lack of effectiveness is, in part, because bacterial species are generally antigenically diverse and conserved immunogenic surface components can be masked by large structures such as capsules. Identifying tractable therapeutic antibody targets that are generic or specific for particular pathogenic or AMR bacteria would be a valuable addition to our current arsenal of therapeutic options.

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“…Antibody-mediated protection from complement has been observed previously 32,33,34 and is a major concern when it comes to antibody therapy. This observation needs to be considered when targeting bacterial O-antigens by therapeutic mAbs.…”

Section: Binding Phenotypes Correlate With Differences In Serum Resismentioning

confidence: 95%

A novel therapeutic antibody screening method using bacterial high-content imaging reveals functional antibody binding phenotypes ofEscherichia coliST131

Maes

Dyson

Smith

et al. 2020

Preprint

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The increase of antimicrobial resistance (AMR), and lack of new classes of licensed antimicrobials, have made alternative treatment options for AMR pathogens increasingly attractive. Recent studies have demonstrated anti-bacterial efficacy of a humanised monoclonal antibody (mAb) targeting the O25b O-antigen of Escherichia coli ST131. To evaluate the phenotypic effects of antibody binding to diverse clinical E. coli ST131 O25b bacterial isolates in high-throughput, we designed a novel mAb screening method using highcontent imaging (HCI) and image-based morphological profiling to screen a mAb targeting the O25b O-antigen. Screening the antibody against a panel of 86 clinical E. coli ST131 O25:H4 isolates revealed 4 binding phenotypes: no binding (18.60%), weak binding (4.65%), strong binding (69.77%) and strong agglutinating binding (6.98%). Impaired antibody binding could be explained by the presence of insertion sequences or mutations in O-antigen or lipopolysaccharide core biosynthesis genes, affecting the amount, structure or chain length of the O-antigen. The agglutinating binding phenotype was linked with lower O-antigen density, enhanced antibody-mediated phagocytosis and increased serum susceptibly. This study highlights the need to screen candidate mAbs against large panels of clinically relevant isolates, and that HCI can be used to evaluate mAb binding affinity and potential functional efficacy against AMR bacteria.

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A Novel Method of Serum Resistance by Escherichia coli That Causes Urosepsis

Cited by 32 publications

References 16 publications

Glycine, serine and threonine metabolism confounds efficacy of complement-mediated killing

Glycine, serine and threonine metabolism confounds efficacy of complement-mediated killing

A novel therapeutic antibody screening method using bacterial high-content imaging reveals functional antibody binding phenotypes of Escherichia coli ST131

A novel therapeutic antibody screening method using bacterial high-content imaging reveals functional antibody binding phenotypes ofEscherichia coliST131

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