Viable screening targets related to the bacterial cell wall

Silver, Lynn L.

doi:10.1111/nyas.12006

Cited by 52 publications

(64 citation statements)

References 198 publications

(340 reference statements)

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“…Indeed, UppS represents an attractive target due to its essential role in the biosynthesis of the different cell wall elements. To date, there have been no validated inhibitors of UppS but there are some interesting leads (25,37). For instance, various bisphosphonate compounds that mimic diphosphate substrates have been found to inhibit UppS in vitro via competition with substrate for enzyme binding (25,38).…”

Section: Discussionmentioning

confidence: 99%

Antagonism screen for inhibitors of bacterial cell wall biogenesis uncovers an inhibitor of undecaprenyl diphosphate synthase

Farha

Czarny

Myers

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

105

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Drug combinations are valuable tools for studying biological systems. Although much attention has been given to synergistic interactions in revealing connections between cellular processes, antagonistic interactions can also have tremendous value in elucidating genetic networks and mechanisms of drug action. Here, we exploit the power of antagonism in a high-throughput screen for molecules that suppress the activity of targocil, an inhibitor of the wall teichoic acid (WTA) flippase in Staphylococcus aureus. Well-characterized antagonism within the WTA biosynthetic pathway indicated that early steps would be sensitive to this screen; however, broader interactions with cell wall biogenesis components suggested that it might capture additional targets. A chemical screening effort using this approach identified clomiphene, a widely used fertility drug, as one such compound. Mechanistic characterization revealed the target was the undecaprenyl diphosphate synthase, an enzyme that catalyzes the synthesis of a polyisoprenoid essential for both peptidoglycan and WTA synthesis. The work sheds light on mechanisms contributing to the observed suppressive interactions of clomiphene and in turn reveals aspects of the biology that underlie cell wall synthesis in S. aureus. Further, this effort highlights the utility of antagonistic interactions both in high-throughput screening and in compound mode of action studies. Importantly, clomiphene represents a lead for antibacterial drug discovery.

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Section: Discussionmentioning

confidence: 99%

Antagonism screen for inhibitors of bacterial cell wall biogenesis uncovers an inhibitor of undecaprenyl diphosphate synthase

Farha

Czarny

Myers

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

105

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“…In general, however, if the probability of resistance due to mutations developing in target A is P A and in target B, P B , the likelihood that resistance develops in both targets will be given by the conditional probability P A P B , a small number. Indeed, the anti-infective drugs that have been most successful in mono-therapy often have more than one target[24, 25], while all TB, malaria and HIV/AIDS drugs are only now effective in combination therapies, due to resistance[24]. It is, however, already very difficult (and expensive) to find just one new drug or one new drug lead, and the development of two drugs for use in such a combination will be twice as difficult.…”

Section: Multi-target Inhibitorsmentioning

confidence: 99%

Resistance-resistant antibiotics

Oldfield

Feng

2014

Trends in Pharmacological Sciences

112

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New antibiotics are needed because as drug resistance is increasing, the introduction of new antibiotics is decreasing. Here, we discuss six possible approaches to develop ‘resistance-resistant’ antibiotics. First, multi-target inhibitors in which a single compound inhibits more than one target may be easier to develop than conventional combination therapies with two new drugs. Second, inhibiting multiple targets in the same metabolic pathway is expected to be an effective strategy due to synergy. Third, discovering multiple-target inhibitors should be possible by using sequential virtual screening. Fourth, re-purposing existing drugs can lead to combinations of multi-target therapeutics. Fifth, targets need not be proteins. Sixth, inhibiting virulence factor formation and boosting innate immunity may also lead to decreased susceptibility to resistance. Although it is not possible to eliminate resistance, the approaches reviewed here offer several possibilities for reducing the effects of mutations and in some cases suggest that sensitivity to existing antibiotics may be restored, in otherwise drug resistant organisms.

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“…The cell wall and its biosynthetic machinery are a major target of the action of clinical antibiotics, including fosfomycin, bacitracin, cycloserine, ␤-lactam antibiotics (penicillins and cephalosporins), and glycopeptide antibiotics (vancomycin and teicoplanin) (9)(10)(11). Enterococci and many other Gram-positive pathogenic bacteria are resistant to a wide spectrum of antibiotics and can often be treated only with specific ␤-lactam antibiotics or with vancomycin (12)(13)(14).…”

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confidence: 99%

Substrate Inhibition of VanA byd-Alanine Reduces Vancomycin Resistance in a VanX-Dependent Manner

Aart

Lemmens

Wamel

et al. 2016

Antimicrob Agents Chemother

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Infectious diseases caused by multidrug-resistant (MDR) pathogens are spreading rapidly and are among the biggest threats to human health (1-4). A particular problem with drug discovery from microbial sources is the high frequency of rediscovery of known compounds, which necessitates new approaches to replenish the antimicrobial drug pipelines (5-7). To deal with the increasing antibiotic resistance, novel antibiotics are called for, or alternatively, the life spans of the current drugs must be prolonged by compounds counteracting resistance. Exemplary is amoxicillin-clavulanic acid (Augmentin), which is a combination of a ␤-lactam antibiotic (amoxicillin) and a ␤-lactamase inhibitor (clavulanic acid) (8).The cell wall and its biosynthetic machinery are a major target of the action of clinical antibiotics, including fosfomycin, bacitracin, cycloserine, ␤-lactam antibiotics (penicillins and cephalosporins), and glycopeptide antibiotics (vancomycin and teicoplanin) (9-11). Enterococci and many other Gram-positive pathogenic bacteria are resistant to a wide spectrum of antibiotics and can often be treated only with specific ␤-lactam antibiotics or with vancomycin (12-14). Vancomycin resistance was first discovered in the 1950s (15). Vancomycin resistance is exchanged between bacteria via movable elements such as transposon Tn1546, which is carried by many vancomycin-resistant enterococci (VRE) (16). The most common forms of transferable vancomycin resistance are the VanA-and VanB-type resistance, the expression of which is inducible by vancomycin. VanA-type strains are resistant to high levels of vancomycin as well as to another glycopeptide antibiotic, teicoplanin, while VanB-type strains show only inducible resistance to vancomycin but retain susceptibility to teicoplanin (17). While vancomycin resistance is most prevalent in enterococci (18), resistance has spread to methicillin-resistant Staphylococcus aureus (MRSA) (19). (15,23). The vancomycin resistance gene cluster provides resistance to both vancomycin and teicoplanin and is located on the genome of the vancomycin producer Amycolatopsis mediterranei (24,25) as well as that of other actinomycetes, including the model species Streptomyces coelicolor A3 (26, 27).Streptomycetes are Gram-positive soil bacteria with a complex multicellular life style (28-30). Streptomycetes are a major source of antibiotics and many other natural products of medical and biotechnological importance, such as anticancer, antifungal, or herbicidal compounds (31, 32). Due to the competitive environment of the soil, these microorganisms readily exchange genetic

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Viable screening targets related to the bacterial cell wall

Cited by 52 publications

References 198 publications

Antagonism screen for inhibitors of bacterial cell wall biogenesis uncovers an inhibitor of undecaprenyl diphosphate synthase

Antagonism screen for inhibitors of bacterial cell wall biogenesis uncovers an inhibitor of undecaprenyl diphosphate synthase

Resistance-resistant antibiotics

Substrate Inhibition of VanA byd-Alanine Reduces Vancomycin Resistance in a VanX-Dependent Manner

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