Molecular basis of antimicrobial resistance in Mycoplasma genitalium

Schalk, Thomas Van der; Braam, Joyce F; Kusters, Johannes G.

doi:10.1016/j.ijantimicag.2020.105911

Cited by 28 publications

(32 citation statements)

References 103 publications

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“…Inappropriate or delayed treatments could lead to bacterial persistence and sequelae including pelvic inflammatory diseases, reactive arthritis, ectopic pregnancy and infertility [2,3]. The current use of broad-spectrum azithromycin as a first-line antibiotic therapy for treating Chlamydia has been reported to cause extensive antibacterial resistance in commonly co-infected bacteria such as Mycoplasma genitalium [4,5] and Neisseria gonorrhoeae [6][7][8], both of which have emerged as superbugs with limited treatment options. Therefore, developing narrow-spectrum antibacterial agents can reduce the spread of antibacterial resistance in clinically relevant infections.…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis and biological evaluation of P2-modified proline analogues targeting the HtrA serine protease in Chlamydia

Hwang

Strange

Mazraani

et al. 2022

European Journal of Medicinal Chemistry

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High temperature requirement A (HtrA) serine proteases have emerged as a novel class of antibacterial target, which are crucial in protein quality control and are involved in the pathogenesis of a wide array of bacterial infections. Previously, we demonstrated that HtrA in Chlamydia is essential for bacterial survival, replication and virulence. Here, we report a new series of proline (P2)-modified inhibitors of Chlamydia trachomatis HtrA (CtHtrA) developed by proline ring expansion and Cγ-substitutions. The structure-based drug optimization process was guided by molecular modelling and in vitro pharmacological evaluation of inhibitory potency, selectivity and cytotoxicity. Compound 25 from the first-generation 4-substituted proline analogues increased antiCtHtrA potency and selectivity over human neutrophil elastase (HNE) by approximately 6-and 12-fold, respectively, relative to the peptidic lead compound 1. Based on this compound, second-generation substituted proline residues containing 1,2,3triazole moieties were synthesized by regioselective azide-alkyne click chemistry. Compound 49 demonstrated significantly improved antichlamydial activity in whole cell assays, diminishing the bacterial infectious progeny below the detection limit at the lowest dose tested. Compound 49 resulted in approximately 9-and 22-fold improvement in the inhibitory potency and selectivity relative to 1, respectively. To date, compound 49 is the most potent HtrA inhibitor developed against Chlamydia spp. a Relative inhibition against CtHtrA is the ratio of IC50 CtHtrA(1) to IC50 CtHtrA (compound).b Relative inhibition against HNE is the ratio of IC50 HNE (1) to IC50 HNE (compound).

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Section: Introductionmentioning

confidence: 99%

Design, synthesis and biological evaluation of P2-modified proline analogues targeting the HtrA serine protease in Chlamydia

Hwang

Strange

Mazraani

et al. 2022

European Journal of Medicinal Chemistry

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“…The emergence of M. genitalium fluoroquinolone resistance has triggered a growing concern in the Western Pacific region, with prevalence estimates of fluoroquinolone-associated resistance mutations in parC at 13.6% and 47.1% reported from Australia and Japan, respectively 8,9 . Fluoroquinolone resistance is associated with specific SNPs in the quinolone resistance–determining region (QRDR) of the topoisomerase IV ( parC ) and the DNA gyrase ( gyrA ) genes 6 . Mutations in QRDR have been linked to amino acids S83 and D87 of parC , and M95 and D99 of gyrA 6,8 …”

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confidence: 99%

“…Fluoroquinolone resistance is associated with specific SNPs in the quinolone resistance–determining region (QRDR) of the topoisomerase IV ( parC ) and the DNA gyrase ( gyrA ) genes 6 . Mutations in QRDR have been linked to amino acids S83 and D87 of parC , and M95 and D99 of gyrA 6,8 …”

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confidence: 99%

“…7 Moxifloxacin regimens have been recommended as a second-line treatment option for persistent M. genitalium infections after azithromycin treatment or in cases of confirmed azithromycin-resistant M. genitalium. 6 The emergence of M. genitalium fluoroquinolone resistance has triggered a growing concern in the Western Pacific region, with prevalence estimates of fluoroquinolone-associated resistance mutations in parC at 13.6% and 47.1% reported from Australia and Japan, respectively. 8,9 Fluoroquinolone resistance is associated with specific SNPs in the quinolone resistance-determining region (QRDR) of the topoisomerase IV (parC) and the DNA gyrase (gyrA) genes.…”

mentioning

confidence: 99%

“…8,9 Fluoroquinolone resistance is associated with specific SNPs in the quinolone resistance-determining region (QRDR) of the topoisomerase IV (parC) and the DNA gyrase (gyrA) genes. 6 Mutations in QRDR have been linked to amino acids S83 and D87 of parC, and M95 and D99 of gyrA. 6,8 Sequence-based molecular typing of M. genitalium, used to determine strain diversity, is a powerful tool for epidemiological surveillance.…”

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confidence: 99%

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