A New Multidrug-Resistant Strain of <i>Neisseria gonorrhoeae</i> in Australia

Lahra, Monica M; Ryder, Nathan; Whiley, David M.

doi:10.1056/nejmc1408109

Cited by 134 publications

(66 citation statements)

References 5 publications

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“…FC428 belonged to MLST sequence type 1903 (ST1903) and NG-MAST ST3435, which differ from the previously described ceftriaxone-resistant gonococcal strains (4)(5)(6)(7)(8). For example, MLST ST1903 differs by two and three loci from ST7363 and ST1901, respectively (Table 1).…”

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confidence: 99%

“…Four different ceftriaxone-resistant N. gonorrhoeae strains previously isolated in Japan (H041 [4] and GU140106 [5]), France (6) and Spain (F89 [7]), and Australia (A8806 [8]) have been characterized in detail. None of these strains have spread widely nationally or internationally.…”

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confidence: 99%

“…The penA allele of FC428 (penA FC428 ) was sequenced as previously described (13) to investigate the relatedness with the penA alleles of the previously reported ceftriaxone-resistant gonococcal strains (H041, GU140106, F89, and A8806 [4][5][6][7][8]). The deduced amino acid sequence of PBP 2 in FC428 elucidated a shared trait with the ceftriaxone-resistant strains GU140106 (5) and A8806 (8).…”

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New Ceftriaxone- and Multidrug-Resistant Neisseria gonorrhoeae Strain with a Novel Mosaic penA Gene Isolated in Japan

Nakayama

Shimuta

Furubayashi³

et al. 2016

Antimicrob Agents Chemother

160

144

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We have characterized in detail a new ceftriaxone-and multidrug-resistant Neisseria gonorrhoeae strain (FC428) isolated in Japan in 2015. FC428 differed from previous ceftriaxone-resistant strains and contained a novel mosaic penA allele encoding a new mosaic penicillin-binding protein 2 (PBP 2). However, the resistance-determining 3=-terminal region of penA was almost identical to the regions of two previously reported ceftriaxone-resistant strains from Australia and Japan, indicating that both ceftriaxone-resistant strains and conserved ceftriaxone resistance-determining PBP 2 regions might spread.

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New Ceftriaxone- and Multidrug-Resistant Neisseria gonorrhoeae Strain with a Novel Mosaic penA Gene Isolated in Japan

Nakayama

Shimuta

Furubayashi³

et al. 2016

Antimicrob Agents Chemother

160

144

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“…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)(8)(9)(10)(11). With dwindling treatment options and no vaccine, gonorrhea is a serious public health concern that warrants further research.…”

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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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“…The addition of azithromycin to ceftriaxone monotherapy in recent years was in response to global trends of increasing ceftriaxone MIC values 5 , increasing reports of treatment failures using ceftriaxone monotherapy, and the emergence of the ceftriaxone resistant strains from Japan in 2010 (the H041 strain) 5 , followed by France then Spain (the F89 strain) 6,7 , and then Australia (the A8806 strain) 8 . The move to dual therapy was a speculative bid, without a strong evidence base, to delay and prevent widespread development and expansion of NG AMR to ceftriaxone in the absence of an ideal alternate treatment 5 .…”

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The Australian Gonococcal Surveillance Programme 1979–2017

2017

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Neisseria gonorrhoeae (NG) is an important human bacterial pathogen responsible for more than 78million infections per annum globally1. In Australia and elsewhere, NG infection rates are increasing and, critically, antimicrobial resistance (AMR) in NG poses a substantial threat to health security2. In response, the Australian Gonococcal Surveillance Programme (AGSP) was established in 1979, and has steadfastly evolved since that time to meet the challenges of continuously emerging AMR (Figure 1).

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A New Multidrug-Resistant Strain of Neisseria gonorrhoeae in Australia

Cited by 134 publications

References 5 publications

New Ceftriaxone- and Multidrug-Resistant Neisseria gonorrhoeae Strain with a Novel Mosaic penA Gene Isolated in Japan

New Ceftriaxone- and Multidrug-Resistant Neisseria gonorrhoeae Strain with a Novel Mosaic penA Gene Isolated in Japan

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

The Australian Gonococcal Surveillance Programme 1979–2017

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