Identification of TbpA Residues Required for Transferrin-Iron Utilization by
            <i>Neisseria gonorrhoeae</i>

Noto, Jennifer M.; Cornelissen, Cynthia Nau

doi:10.1128/iai.00020-08

Cited by 36 publications

(41 citation statements)

References 64 publications

(60 reference statements)

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“…This pathogen also requires iron for growth and has multiple mechanisms for acquiring iron, including high-affinity receptors for both transferrin and lactoferrin [14,32,33]. We attempted to determine whether natural and laboratory strains lacking lactoferrin or transferrin receptors were inhibited by the INPs and, if so, could the inhibition be reversed by the iron-rich form of either lactoferrin or transferrin.…”

Section: Discussionmentioning

confidence: 99%

Candidate vaginal microbicides with activity against Chlamydia trachomatis and Neisseriagonorrhoeae

Chu

Slepenkin

Elofsson

et al. 2010

International Journal of Antimicrobial Agents

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Vaginal microbicides with activity towards organisms that cause sexually transmitted infections have been proposed as a strategy to reduce transmission. Small-molecule inhibitors of Chlamydia trachomatis serovar D belonging to the class of salicylidene acylhydrazides (INPs) have been shown to work through a mechanism that involves iron restriction. Expanding on this work, ten INPs were tested against a lymphogranuloma venereum strain of C. trachomatis serovar L2, Neisseria gonorrhoeae, and hydrogen peroxide-producing Lactobacillus crispatus and Lactobacillus jensenii. Seven INPs had minimal inhibitory concentrations (MICs) and minimal bactericidal concentrations of <50 µM towards C. trachomatis L2. Three INPs had an MIC <12.5 µM against N. gonorrhoeae. Inhibition by was reversed by iron, holo-transferrin and holo-lactoferrin but not by the iron-poor forms of these compounds. The compounds exhibited no bactericidal activity toward Lactobacillus. The INPs were not cytotoxic to HeLa 229 cells. When INP 0341 was tested in a mouse model of a Chlamydia vaginal infection there was a significant reduction in the number of mice shedding C. trachomatis up to 4 days after infection (P < 0.01). In summary, select INPs are promising vaginal microbicide candidates as they inhibit the growth of two common sexually transmitted organisms in vitro, are active in a mouse model against C. trachomatis, are not cytotoxic and do not inhibit organisms that compose the normal vaginal flora.

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Section: Discussionmentioning

confidence: 99%

Candidate vaginal microbicides with activity against Chlamydia trachomatis and Neisseriagonorrhoeae

Chu

Slepenkin

Elofsson

et al. 2010

International Journal of Antimicrobial Agents

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“…whereas the pathogen Actinobacillus (Haemophilus) pleuropneumoniae is able to bind and use pig, but not human, transferrin as an iron source 39,41. Two proteins, TbpA and TbpB work together as the functional transferrin receptor 42. TbpA serves as the outer membrane pore through which iron, removed from the host's transferrin, enters the bacterial cell periplasm.…”

Section: Iron Acquisition Pathwaysmentioning

confidence: 99%

Microbial Iron Acquisition: Marine and Terrestrial Siderophores

2009

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“…Tf-iron uptake assays were performed as described previously (32)(33)(34)(35). Briefly, apo-human Tf (Sigma) was saturated to 20% with 55 Fe (Perkin-Elmer).…”

Section: Figmentioning

confidence: 99%

Beyond the Crystal Structure: Insight into the Function and Vaccine Potential of TbpA Expressed by Neisseria gonorrhoeae

et al. 2015

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bNeisseria gonorrhoeae, the causative agent of the sexually transmitted infection gonorrhea, is not preventable by vaccination and is rapidly developing resistance to antibiotics. However, the transferrin (Tf) receptor system, composed of TbpA and TbpB, is an ideal target for novel therapeutics and vaccine development. Using a three-dimensional structure of gonococcal TbpA, we investigated two hypotheses, i.e., that loop-derived antibodies can interrupt ligand-receptor interactions in the native bacterium and that the loop 3 helix is a critical functional domain. Preliminary loop-derived antibodies, as well as optimized second-generation antibodies, demonstrated similar modest ligand-blocking effects on the gonococcal surface but different effects in Escherichia coli. Mutagenesis of loop 3 helix residues was employed, generating 11 mutants. We separately analyzed the mutants' abilities to (i) bind Tf and (ii) internalize Tf-bound iron in the absence of the coreceptor TbpB. Single residue mutations resulted in up to 60% reductions in ligand binding and up to 85% reductions in iron utilization. All strains were capable of growing on Tf as the sole iron source. Interestingly, in the presence of TbpB, only a 30% reduction in Tf-iron utilization was observed, indicating that the coreceptor can compensate for TbpA impairment. Complete deletion of the loop 3 helix of TbpA eliminated the abilities to bind Tf, internalize iron, and grow with Tf as the sole iron source. Our studies demonstrate that while the loop 3 helix is a key functional domain, its function does not exclusively rely on any single residue. N eisseria gonorrhoeae, the causative agent of the sexually transmitted infection gonorrhea (1), affects approximately 106 million people worldwide according to WHO estimates (2), with Ͼ300,000 cases of gonorrhea reported each year in the United States alone (3). A troubling contributor to these statistics is that infection with this bacterium does not result in any protective immunity (4). Additionally, approximately 50% of the women infected with the gonococcus are asymptomatic, resulting in increased spread and more severe clinical outcomes following infection (5). Most concerning of all is that the gonococcus has become increasingly drug resistant, with mounting evidence to suggest that current pharmacotherapies may soon be rendered obsolete (6, 7). To date, the characteristics of at least three multidrugresistant isolates have been published, all of which are fully resistant to ceftriaxone, the core component of the currently recommended combination therapy for the treatment of gonorrhea (7-11). With dwindling treatment options and no vaccine, gonorrhea is a serious public health concern that warrants further research.One approach to the development of therapeutics has been to study how the gonococcus acquires iron, an essential nutrient for nearly all microorganisms (12). During human infection, microorganisms are confronted with the challenge of obtaining iron in an environment that has evolved to specifically...

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Identification of TbpA Residues Required for Transferrin-Iron Utilization by Neisseria gonorrhoeae

Cited by 36 publications

References 64 publications

Candidate vaginal microbicides with activity against Chlamydia trachomatis and Neisseriagonorrhoeae

Candidate vaginal microbicides with activity against Chlamydia trachomatis and Neisseriagonorrhoeae

Microbial Iron Acquisition: Marine and Terrestrial Siderophores

Beyond the Crystal Structure: Insight into the Function and Vaccine Potential of TbpA Expressed by Neisseria gonorrhoeae

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