Functional insights into <i>Streptomyces</i> isolates containing both clavulanic acid-like and carbapenem biosynthetic gene clusters
Bibliographic record
Abstract
ABSTRACT β-Lactam antibiotics and β-lactamase inhibitor combinations are essential for combating antimicrobial resistance, with many β-lactams, including clavulanic acid (CA), themselves being products of specialized metabolic pathways in bacteria. CA is a potent β-lactamase inhibitor, and in known producers such as Streptomyces clavuligerus , it is co-produced with the β-lactam antibiotic cephamycin C, and their biosynthetic gene clusters (BGCs) are always located adjacent on the chromosome. However, CA-like BGCs have also been identified in other bacteria, often without an accompanying cephamycin C BGC. Similarly, carbapenem BGCs (a subclass of β-lactams), such as those responsible for producing MM 4550, a member of the olivanic acid complex with both antibiotic and β-lactamase inhibitory properties, are also found in Streptomyces species. This study investigated antimicrobial and β-lactamase inhibitory activity production in Streptomyces pratensis and 10 environmental Streptomyces isolates (JAC strains) containing CA-like and MM 4550-like BGCs but lacking cephamycin C BGCs. While the examined isolates do not produce CA, they synthesize predicted monocyclic β-lactam precursors of CA, which potentially represent a previously unrecognized, primordial form of β-lactamase inhibitor. Several JAC isolates also exhibited both β-lactamase inhibitory and β-lactam antibiotic activities, indicating that the carbapenem BGC is active in these strains. Gene disruption analysis confirmed that MM 4550-like carbapenem BGCs contribute to both antimicrobial and β-lactamase inhibitory activities, whereas CA-like clavam BGCs only contribute to β-lactamase inhibition. The findings also suggest that both β-lactam BGC types co-occur in nature more frequently than previously recognized, possibly with functional significance and potential applications in the discovery of novel antibiotic-inhibitor combinations. IMPORTANCE The global rise of antimicrobial resistance calls for innovative strategies to preserve the efficacy of existing antibiotics and identify new therapeutic agents. This study explores naturally occurring β-lactamase inhibitors and antibiotics beyond well-characterized systems. Investigation of clavulanic acid (CA)-like and MM 4550-like biosynthetic gene clusters (BGCs) in Streptomyces pratensis and related environmental isolates revealed a broader occurrence of monocyclic β-lactam precursors and dual-function carbapenems in nature. These findings offer new insights into β-lactam co-production and further indicate that unlinked β-lactam BGCs may have functional significance. The study also highlights the importance of exploring silent counterparts of known BGCs as potential sources of bioactive metabolites, enhancing our understanding of β-lactam BGC diversity and evolution. Notably, it identifies β-lactamase inhibitor and antibiotic-producing strains, opening new avenues for discovering antibiotic-inhibitor combinations of relevance.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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 teacher head, 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".