Self-resistance mechanism to acyldepsipeptide antibiotics in the <i>Streptomyces</i> producer
Bibliographic record
Abstract
ABSTRACT Clp proteases are ubiquitous in bacteria and play an important role in regulatory proteolysis and in maintaining protein homeostasis within the bacterial cell. They consist of a tetradecameric, proteolytic ClpP core and associated AAA+ Clp-ATPases. The Clp system of Streptomyces is unusually complex, comprising up to five ClpP homologs (ClpP1–ClpP5) and three Clp-ATPases (ClpX, ClpC1, and ClpC2). Streptomycetes produce a plethora of secondary metabolites, including potent acyldepsipeptide (ADEP) antibiotics, which target ClpP. We have previously reported on the operation mode of the Streptomyces ClpP1P2 protease and identified a novel clpP gene (named clpP ADEP ) as a resistance determinant encoded near the ADEP biosynthesis gene cluster. However, the molecular function of ClpP ADEP remains enigmatic. Here, we report on the molecular self-resistance mechanism to ADEP via ClpP ADEP and its interaction with the Clp system in the ADEP producer Streptomyces hawaiiensis NRRL 15010. By combining cell-based and in vitro studies, we show that ClpP ADEP interferes with the formation of the ClpP1P2 complex and inhibits the proteolytic activity of ClpP1. Moreover, ClpP ADEP forms a functional complex with ClpP2 and Clp-ATPases. By these means, ClpP ADEP protects the producer cell against ADEP in a two-pronged approach. On the one hand, it prevents ADEP from corrupting ClpP1 to degrade delicate essential proteins and polypeptides. On the other hand, ClpP ADEP ensures the survival of the producer cells by maintaining the housekeeping function of the Clp protease in regulatory proteolysis. IMPORTANCE Acyldepsipeptide (ADEP) antibiotics kill bacteria using an unusual mechanism of action, that is, the multilayered deregulation and activation of ClpP, the proteolytic core of the bacterial Clp protease. ADEP is highly effective in killing Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). Considering the elaborate mechanism of action of ADEP as well as the complexity of the essential Clp system in Streptomyces with up to five ClpP homologs as potential ADEP targets, the question arises: how does the producer ensure self-resistance in such a complex system? Here, we describe the molecular mechanism of self-resistance to ADEP in the producer Streptomyces hawaiiensis NRRL 15010, which is based on the presence of a phylogenetically distinct ClpP protein in the genome of the ADEP producer strain.
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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) | 0.000 | 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".