Arylomycins A and B, New Biaryl-bridged Lipopeptide Antibiotics Produced by Streptomyces sp. Tue 6075. II. Structure Elucidation.

Höltzel, Alexandra; Schmid, Dietmar G.; Nicholson, Graeme; Stevanović, Stefan; Schimana, Judith; Gebhardt, Klaus; Fiedler, Hans‐Peter; Jung, Günther

doi:10.7164/antibiotics.55.571

Cited by 85 publications

(79 citation statements)

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“…At the time of the completion of this work, a literature search revealed that this family of lipoglycopeptides is novel. Subsequently, we learned that structures of a similar family of lipopeptides, called arylomycins, have been disclosed in a conference proceeding (35) followed by a publication (36). The major structural difference is the absence of the sugar unit in arylomycins.…”

Section: Resultsmentioning

confidence: 99%

Novel Lipoglycopeptides as Inhibitors of Bacterial Signal Peptidase I

Kulanthaivel

Kreuzman

Strege

et al. 2004

Journal of Biological Chemistry

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Signal peptidase (SPase) I is responsible for the cleavage of signal peptides of many secreted proteins in bacteria. Because of its unique physiological and biochemical properties, it serves as a potential target for development of novel antibacterial agents. In this study, we report the production, isolation, and structure determination of a family of structurally related novel lipoglycopeptides from a Streptomyces sp. as inhibitors of SPase I. Detailed spectroscopic analyses, including MS and NMR, revealed that these lipoglycopeptides share a common 14-membered cyclic peptide core, an acyclic tripeptide chain, and a deoxy-␣-mannose sugar, but differ in the degree of oxidation of the N-methylphenylglycine residue and the length and branching of the fatty acyl chain. Biochemical analysis demonstrated that these peptides are potent and competitive inhibitors of SPase I with K i 50 to 158 nM. In addition, they showed modest antibacterial activity against a panel of pathogenic Gram-positive and Gram-negative bacteria with minimal inhibitory concentration of 8 -64 M against Streptococcus pneumonniae and 4 -8 M against Escherichia coli. Notably, they mechanistically blocked the protein secretion in whole cells as demonstrated by inhibiting ␤-lactamase release from Staphylococcus aureus. Taken together, the present discovery of a family of novel lipoglycopeptides as potent inhibitors of bacterial SPase I may lead to the development of a novel class of broad-spectrum antibiotics.Proteins destined for secretion in both prokaryotic and eukaryotic organisms are initially synthesized as precursors with an amino-terminal extension known as signal (or leader) peptide. The signal sequence is removed by a signal peptidase (SPase) 1 that is localized in the cytoplasmic membrane in bacteria. Cleavage of precursors by SPase leads to the release of secreted proteins from the outer surface of cytoplasmic membrane. In bacteria, two major SPases, SPase I and SPase II with different cleavage specificities, have been identified. SPase I is responsible for processing the majority of secreted proteins (1-3), and SPase II is exclusively involved in processing glyceride-modified lipoproteins (4).SPase I is an attractive target for development of antibacterial agents because of its unique biochemical and physiological properties. It is essential for bacterial viability and growth as demonstrated by gene knockout and other genetic experiments (5-8). It is widely distributed in both Gram-positive and Gramnegative bacteria, as well as in Chlamydia. Genes encoding SPase I have been cloned and sequenced from different bacterial species, including many of clinically relevant bacteria (8, 9). The active domain of bacterial SPase I is exposed to the surface of cytoplasmic membrane as revealed by sequence and topological analysis (10 -12), and thus is accessible to potential inhibitors. In addition, SPases from bacteria and eukaryotic cells are different in composition, location, and possibly catalytic mechanism (13-17). These differences make it ...

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Section: Resultsmentioning

confidence: 99%

Novel Lipoglycopeptides as Inhibitors of Bacterial Signal Peptidase I

Kulanthaivel

Kreuzman

Strege

et al. 2004

Journal of Biological Chemistry

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“…1) (11)(12)(13). Despite the essentiality, conservation, and relative accessibility of SPase (10,14), the arylomycins were initially reported to have a narrow spectrum of activity (12,13).…”

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A Putative Cro-Like Repressor Contributes to Arylomycin Resistance in Staphylococcus aureus

Craney

Romesberg

2015

Antimicrob Agents Chemother

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Antibiotic-resistant bacteria are a significant public health concern and motivate efforts to develop new classes of antibiotics. One such class of antibiotics is the arylomycins, which target type I signal peptidase (SPase), the enzyme responsible for the release of secreted proteins from their N-terminal leader sequences. Despite the essentiality, conservation, and relative accessibility of SPase, the activity of the arylomycins is limited against some bacteria, including the important human pathogen Staphylococcus aureus. To understand the origins of the limited activity against S. aureus, we characterized the susceptibility of a panel of strains to two arylomycin derivatives, arylomycin A-C 16 and its more potent analog arylomycin M131. We observed a wide range of susceptibilities to the two arylomycins and found that resistant strains were sensitized by cotreatment with tunicamycin, which inhibits the first step of wall teichoic acid synthesis. To further understand how S. aureus responds to the arylomycins, we profiled the transcriptional response of S. aureus NCTC 8325 to growth-inhibitory concentrations of arylomycin M131 and found that it upregulates the cell wall stress stimulon (CWSS) and an operon consisting of a putative transcriptional regulator and three hypothetical proteins. Interestingly, we found that mutations in the putative transcriptional regulator are correlated with resistance, and selection for resistance ex vivo demonstrated that mutations in this gene are sufficient for resistance. The results begin to elucidate how S. aureus copes with secretion stress and how it evolves resistance to the inhibition of SPase.T he widespread use of antibiotics imposes a relentless selection pressure on bacteria that has driven the evolution of multidrug resistance in many pathogens, and novel classes of antibiotics are needed (1, 2). Staphylococcus aureus has emerged as a particular health concern due to its ability to cause a wide range of infections, ranging from superficial lesions such as skin abscesses and wound infections to more systemic and life-threatening conditions such as osteomyelitis, endocarditis, pneumonia, septicemia, and toxinoses. To infect different tissues, S. aureus relies on the secretion of virulence factors that facilitate adhesion and colonization, promote dissemination, facilitate the evasion of the host immune response, and scavenge nutrients and minerals from the environment (3-6). The majority of proteins destined for export out of the cytoplasm are synthesized as preproteins with N-terminal signal peptide sequences, which target them to the general secretory (Sec) pathway (7-9), and these leader peptides ultimately must be removed by the proteolytic activity of type I signal peptidase (SPase) (10).SPase has long been appreciated as a promising target for antibiotic therapy, and a search for inhibitors led to the identification in 2002 of the arylomycin family of natural product lipopeptide antibiotics from a strain of Streptomyces (Fig. 1) (11-13). Despite the essentiali...

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“…The arylomycins are a class of natural product antibiotics isolated in 2002 and subsequently shown to inhibit Escherichia coli SPase in vitro (41,95). We have synthesized a variety of arylomycins, including the derivative arylomycin A-C 16 ( Fig.…”

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confidence: 99%