Using sialic acid analogues to define the molecular basis of complement resistance mediated by sialylation of neisseria gonorrhoeae lipopolysaccharide and to design novel therapeutics
Bibliographic record
Abstract
Substitution of Neisseria gonorrhoeae lacto-N-neotetraose (LNT) lipooligosaccharide (LOS) with Neu5Ac confers on the bacterium the ability to evade complement-mediated killing by enhancing binding of the alternative pathway inhibitor, factor H (FH), and also reducing binding of specific IgG. We utilized the CMP salts of six sialic acid analogues, Neu5Gc, Neu5Ac9Ac, Neu5Ac9Az, Neu5Gc8Me, Leg5Ac7Ac and Pse5Ac7Ac, to characterize the substrate specificity for gonococcal LOS sialyltransferase (Lst) and define the structural requirements of sialic acid-mediated complement resistance. All analogues, except Pse5Ac7Ac, served as substrates for gonococcal Lst and were incorporated on to LNT LOS. Only Neu5Gc incorporation yielded FH binding and high-level serum resistance comparable with Neu5Ac-substituted LOS. Neu5Ac9Ac and Neu5Gc8Me permitted resistance only to low, but not high complement concentrations, while Neu5Ac9Az and Leg5Ac7Ac did not confer any resistance to complement. Neu5Ac9Ac addition resulted in low-level FH binding (~20% of the levels seen with Neu5Ac and Neu5Gc), but addition of none of the remaining analogues showed detectable FH binding by FACS. The extent of classical pathway inhibition (measured by IgG binding and C4 deposition) was proportional to serum resistance. Adding CMP-Neu5A9Az or CMP-Leg5Ac7Ac to bacteria within 15 min of adding CMP-Neu5Ac did not block FH binding facilitated by Neu5Ac, but blocked classical pathway suppression and serum resistance mediated by Neu5Ac on strain F62 and a high-level ceftriaxone-resistant isolate called H041, even when Neu5Ac was present at a 10- 100-fold molar excess. Administration of CMP-Leg5Ac7Ac intravaginally significantly reduced the duration of infection (median time to clearance 6 and 10 days in treated and untreated mice, respectively; P<0.0001) and bacterial burdens (P=0.0005) in the murine vaginal colonization model of gonorrhea. Collectively, these data shed light on substrate specificity of gonococcal Lst and reveal critical roles for carbon 7, 8 and 9 substitutions on sialic acid for complement inhibition on gonococci. The use of sialic acid analogues to counter gonococcal virulence provides a novel therpeutic strategy against the global threat of multi-drug resistant gonorrhea.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".