Total Synthesis and Antibacterial Testing of the A54556 Cyclic Acyldepsipeptides Isolated from <i>Streptomyces hawaiiensis</i>

Goodreid, Jordan; Wong, Keith S.; Leung, Eman; McCaw, Shannon E.; Gray-Owen, Scott D.; Lough, Alan J.; Houry, Walid; Batey, Robert A.

doi:10.1021/np500158q

Cited by 28 publications

(39 citation statements)

References 45 publications

(50 reference statements)

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“…39,62 Numerous other synthetic chemistry efforts have explored motifs to overcome these limitations, but most have resulted in diminished activity (Figure 4c). 54,[63][64][65][66][67] Given the intimate binding of ADEP in its hydrophobic pocket, this result is perhaps predictable and suggests that modification on the ADEP scaffold may have reached an impasse.…”

Section: Clpp Activatorsmentioning

confidence: 84%

Bacterial proteases, untapped antimicrobial drug targets

2016

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Bacterial proteases are an extensive collection of enzymes that have vital roles in cell viability, stress response and pathogenicity. Although their perturbation clearly offers the potential for antimicrobial drug development, both as traditional antibiotics and anti-virulence drugs, they are not yet the target of any clinically used therapeutics. Here we describe the potential for and recent progress in the development of compounds targeting bacterial proteases with a focus on AAA+ family proteolytic complexes and signal peptidases (SPs). Caseinolytic protease (ClpP) belongs to the AAA+ family of proteases, a group of multimeric barrel-shaped complexes whose activity is tightly regulated by associated AAA+ ATPases. The opportunity for chemical perturbation of these complexes is demonstrated by compounds targeting ClpP for inhibition, activation or perturbation of its associated ATPase. Meanwhile, SPs are also a proven antibiotic target. Responsible for the cleavage of targeting peptides during protein secretion, both type I and type II SPs have been successfully targeted by chemical inhibitors. As the threat of pan-antibiotic resistance continues to grow, these and other bacterial proteases offer an arsenal of novel antibiotic targets ripe for development.

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Section: Clpp Activatorsmentioning

confidence: 84%

Bacterial proteases, untapped antimicrobial drug targets

2016

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“… Structures of A) different ADEP fragments, with published structures 01 and 05 and fragment photoprobe 235 and B) ADEP derivatives 10 , ADEP4, and photoprobes 266 and 288 .…”

Section: Resultsmentioning

confidence: 99%

Acyldepsipeptide Probes Facilitate Specific Detection of Caseinolytic Protease P Independent of Its Oligomeric and Activity State

et al. 2020

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Caseinolytic protease P (ClpP) is a tetradecameric peptidase that assembles with chaperones such as ClpX to gain proteolytic activity. Acyldepsipeptides (ADEPs) are small‐molecule mimics of ClpX that bind into hydrophobic pockets on the apical site of the complex, thereby activating ClpP. Detection of ClpP has so far been facilitated with active‐site‐directed probes which depend on the activity and oligomeric state of the complex. To expand the scope of ClpP labeling, we took a stepwise synthetic approach toward customized ADEP photoprobes. Structure–activity relationship studies with small fragments and ADEP derivatives paired with modeling studies revealed the design principles for suitable probe molecules. The derivatives were tested for activation of ClpP and subsequently applied in labeling studies of the wild‐type peptidase as well as enzymes bearing mutations at the active site and an oligomerization sensor. Satisfyingly, the ADEP photoprobes provided a labeling readout of ClpP independent of its activity and oligomeric state.

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“…A noncanonical (2S,4R)-4-methylproline (MePro) residue present in the ADEP1 macrocycle is replaced by L-proline (Pro) in "factor B"; factor B and ADEP1 are the most abundant ADEP congeners produced by S. hawaiiensis NRRL 15010. ADEP1 exhibits, depending on the organism tested, a 4-to 8-fold higher antibiotic activity than factor B, which highlights MePro as an important feature for antibacterial activity (20,21).…”

mentioning

confidence: 94%

The ADEP Biosynthetic Gene Cluster in Streptomyces hawaiiensis NRRL 15010 Reveals an Accessory clpP Gene as a Novel Antibiotic Resistance Factor

Thomy

Culp

Adámek

et al. 2019

Appl Environ Microbiol

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The increasing threat posed by multiresistant bacterial pathogens necessitates the discovery of novel antibacterials with unprecedented modes of action. ADEP1, a natural compound produced by Streptomyces hawaiiensis NRRL 15010, is the prototype for a new class of acyldepsipeptide (ADEP) antibiotics. ADEP antibiotics deregulate the proteolytic core ClpP of the bacterial caseinolytic protease, thereby exhibiting potent antibacterial activity against Gram-positive bacteria, including multiresistant pathogens. ADEP1 and derivatives, here collectively called ADEP, have been previously investigated for their antibiotic potency against different species, structure-activity relationship, and mechanism of action; however, knowledge on the biosynthesis of the natural compound and producer self-resistance have remained elusive. In this study, we identified and analyzed the ADEP biosynthetic gene cluster in S. hawaiiensis NRRL 15010, which comprises two NRPSs, genes necessary for the biosynthesis of (4S,2R)-4-methylproline, and a type II polyketide synthase (PKS) for the assembly of highly reduced polyenes. While no resistance factor could be identified within the gene cluster itself, we discovered an additional clpP homologous gene (named clpPADEP) located further downstream of the biosynthetic genes, separated from the biosynthetic gene cluster by several transposable elements. Heterologous expression of ClpPADEP in three ADEP-sensitive Streptomyces species proved its role in conferring ADEP resistance, thereby revealing a novel type of antibiotic resistance determinant. IMPORTANCE Antibiotic acyldepsipeptides (ADEPs) represent a promising new class of potent antibiotics and, at the same time, are valuable tools to study the molecular functioning of their target, ClpP, the proteolytic core of the bacterial caseinolytic protease. Here, we present a straightforward purification procedure for ADEP1 that yields substantial amounts of the pure compound in a time- and cost-efficient manner, which is a prerequisite to conveniently study the antimicrobial effects of ADEP and the operating mode of bacterial ClpP machineries in diverse bacteria. Identification and characterization of the ADEP biosynthetic gene cluster in Streptomyces hawaiiensis NRRL 15010 enables future bioinformatics screenings for similar gene clusters and/or subclusters to find novel natural compounds with specific substructures. Most strikingly, we identified a cluster-associated clpP homolog (named clpPADEP) as an ADEP resistance gene. ClpPADEP constitutes a novel bacterial resistance factor that alone is necessary and sufficient to confer high-level ADEP resistance to Streptomyces across species.

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Total Synthesis and Antibacterial Testing of the A54556 Cyclic Acyldepsipeptides Isolated from Streptomyces hawaiiensis

Cited by 28 publications

References 45 publications

Bacterial proteases, untapped antimicrobial drug targets

Bacterial proteases, untapped antimicrobial drug targets

Acyldepsipeptide Probes Facilitate Specific Detection of Caseinolytic Protease P Independent of Its Oligomeric and Activity State

The ADEP Biosynthetic Gene Cluster in Streptomyces hawaiiensis NRRL 15010 Reveals an Accessory clpP Gene as a Novel Antibiotic Resistance Factor

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