Broadening the Spectrum of β-Lactam Antibiotics through Inhibition of Signal Peptidase Type I

Therien, Alex G.; Huber, John D.; Wilson, Kenneth E.; Beaulieu, Patrick; Caron, Alexandre; Claveau, David; Deschamps, Kathleen; Donald, Robert G. K.; Galgoci, Andrew; Gallant, Michel; Gu, Xinchen; Kevin, Nancy J.; LaFleur, J. Lance; Leavitt, Penny; Lebeau-Jacob, Christian; Lee, Suzy S.; Lin, Molly M.; Michels, Anna A.; Ogawa, Aimie M.; Painter, Ronald E.; Parish, Craig A.; Park, Young-Whan; Benton-Perdomo, Liliana; Petcu, Mihai; Phillips, John W.; Powles, Mary Ann; Skorey, Kathryn; Tam, John; Tan, Christopher M.; Young, Katherine; Wong, Simon; Waddell, Sherman T.; Miesel, Lynn

doi:10.1128/aac.00726-12

Cited by 72 publications

(54 citation statements)

References 39 publications

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“…92 A screen for synergizers by the Merck Frosst group of imipenem in MRSA identified two natural product SP-I inhibitors, the arylomycinlike actinocarbamycin and the cyclic peptide krisinomycin (Figure 7a). 93 The logic of synergy likely is the result of inhibition of secretion of β-lactamases that inactivate imipenem. Synthesis of actinocarbamycin generated M131 (Figure 7a) with improved in vitro inhibition of the MRSA SP-I, SpsB and imipenem synergy activity in murine models of MRSA infection.…”

Section: Bacterial Proteases Untapped Antimicrobial Drug Targetsmentioning

confidence: 99%

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: Bacterial Proteases Untapped Antimicrobial Drug Targetsmentioning

confidence: 99%

Bacterial proteases, untapped antimicrobial drug targets

2016

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“…Thus, it seems likely that in the actual context of an infection, the arylomycins may possess a more potent and broad-spectrum activity than predicted based on MICs, especially against Gram-negative bacteria, which possess a single SPase and where high levels of secretion are typically required for the protein-rich periplasm and outer membrane of these organisms (65,66). Along with the previously demonstrated activity of the arylomycins against many Gram-positive bacteria (25,67), this reinforces the idea that they may be promising candidates for further development as therapeutics.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, compared to Gram-positive organisms, a far greater number of proteins are processed by SPase in Gram-negative bacteria, which must maintain a protein-rich periplasm and outer membrane (65,66), suggesting that targeting SPase may be a particularly effective strategy to combat these pathogens. Our previous demonstration that the arylomycin class of antibiotics, which act by inhibiting SPase, has the potential for broad-spectrum activity (14,25,58,67), including against Gramnegative pathogens, suggests that they might be interesting for development as antibiotics. However, this will require an understanding of the varying susceptibilities of different bacteria and their physiological origins.…”

Section: Discussionmentioning

confidence: 99%

Origins of Yersinia pestis Sensitivity to the Arylomycin Antibiotics and the Inhibition of Type I Signal Peptidase

Steed

Liu

Wasbrough

et al. 2015

Antimicrob Agents Chemother

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bYersinia pestis is the etiologic agent of the plague. Reports of Y. pestis strains that are resistant to each of the currently approved first-line and prophylactic treatments point to the urgent need to develop novel antibiotics with activity against the pathogen. We previously reported that Y. pestis strain KIM6؉, unlike most Enterobacteriaceae, is susceptible to the arylomycins, a novel class of natural-product lipopeptide antibiotics that inhibit signal peptidase I (SPase). In this study, we show that the arylomycin activity is conserved against a broad range of Y. pestis strains and confirm that it results from the inhibition of SPase. We next investigated the origins of this unique arylomycin sensitivity and found that it does not result from an increased affinity of the Y. pestis SPase for the antibiotic and that alterations to each component of the Y. pestis lipopolysaccharide-O antigen, core, and lipid A-make at most only a small contribution. Instead, the origins of the sensitivity can be traced to an increased dependence on SPase activity that results from high levels of protein secretion under physiological conditions. These results highlight the potential of targeting protein secretion in cases where there is a heavy reliance on this process and also have implications for the development of the arylomycins as an antibiotic with activity against Y. pestis and potentially other Gram-negative pathogens.T he emergence of multidrug-resistant bacteria, especially Gram-negative pathogens, is a major health concern that can be combated only by the continued development of new antibiotics, particularly ones that act via novel mechanisms of action to limit the potential for cross-resistance. Yersinia pestis, a Gramnegative bacterium and the causative agent of plague, is of particular historical significance due to the mortality and social havoc wreaked by at least three major pandemics (1, 2). Today, plague continues to pose a threat, even in developed countries (3), and while Y. pestis infections are now treatable with available antibiotics, delays in the initiation of effective therapy, as can be caused by resistance to the employed antibiotic, results in significantly increased mortality (4). Thus, reports of Y. pestis strains that are resistant to first-line antibiotic therapies (5-7) are troubling, and the all but certain continued evolution of these strains toward resistance to all available antibiotics threatens to return the plague agent to its historical position as an important pathogen. This threat is unlikely to abate until new, effective antibiotics are discovered and developed; however, no new class of antibiotics with activity against Gram-negative bacteria has been approved in over 40 years (8). Moreover, a recent report by the Infectious Diseases Society of America (IDSA) identified only seven new candidate antibiotics that have progressed into clinical development for the treatment of multidrug-resistant Gram-negative bacilli since 2010 (9).A general challenge in developing antibiotics again...

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“…Researchers discover new agents that restore the activity of beta-lactams against MRSA, an approach that has led to the discovery of two classes of natural product antibiotics, a cyclic depsipeptide (krisynomycin) and a lipoglycopeptide (actinocarbasin) [64], which potentiate the activity of imipenem against MRSA strain COL. Researchers reported that these imipenem synergists are inhibitors of the bacterial type I signal peptidase SpsB, a serine protease that is required for the secretion of proteins that are exported through the Sec and Tat systems [65].…”

Section: Broadening the Spectrum Of Beta-lactam Antibioticsmentioning

confidence: 99%