Innovative strategies are had a need to combat drug resistance associated

Innovative strategies are had a need to combat drug resistance associated with methicillin-resistant (MRSA). -lactam antibiotics, a broad and historically important class of antibiotics spanning penicillin, methicillin, and the more powerful carbapenems, including imipenem, which kill bacteria by inhibiting synthesis and chemical cross-linking of peptidoglycan (PG), a cell wall polymer, leading to weakening of the cell wall and cell lysis (Walsh, 2003). The development of antibiotic combination agents has proven to be a highly successful therapeutic strategy to combat drug resistance, particularly against drug resistant Gram-negative bacteria (Drawz and Bonomo, 2010). Paramount to the rationale of combination agents is the increased potency and efficacy achieved by their combined effects. Ideally, this is achieved by the synergistic bioactivity of both agents affecting two interdependent cellular processes required for cell growth as well as the targeted inactivation of the resistance mechanism to the first agent by the combination agent (Tan et al., 2012). Applying a systems biology approach to discovering synergistic brokers with this therapeutic potential is usually highly warranted; lethal or even growth-crippling chemical genetic interactions spotlight a cellular network of interdependent biological processes and potential drug targets from which combination brokers may be rationally discovered (Andrusiak et al., 2012; Costanzo et al., 2010; Nichols et al., 2011). We and others have adopted this approach to identify genetic mutations that restore -lactam activity against MRSA, and as such, predict that cognate inhibitors of these -lactam potentiation targets may similarly restore the efficacy of the -lactam (de Lencastre et al., 1999; Berger-Bachi and Rohrer, 2002, Huber et al., 2009; Lee et al., 2011; Tan et al., 2012). Indeed, several Rabbit Polyclonal to HSF2 cellular processes contribute to buffering MRSA from the effects of -lactams, including normal synthesis of a second cell wall polymer, wall teichoic acid (WTA) (Campbell GS-9350 et al., 2011; Lee et al., 2011). In support of this notion, target-specific inhibitors of this process, such as tunicamycin (Komatsuzawa et al., 1994; Campbell et al, 2011), an exquisitely selective inhibitor of GS-9350 TarO, responsible for the first step in WTA synthesis (Swoboda et al., 2009), was found to be highly synergistic in combination with -lactams. WTA is a Gram-positive specific anionic glycophosphate cell wall polymer of roughly equal abundance to PG. Unlike PG, however, WTA is not required for cell viability (Weidenmaier et al., 2004; GS-9350 D’Elia et al., 2009b) but plays important functions in cell growth, division, morphology, and as a virulence factor (Schirner et al., 2009; Swoboda et al., 2010; Atilano et al., 2010; Campbell et al., 2011; Dengler et al., 2012, Weidenmaier and Peschel, 2008). WTA polymers are sequentially synthesized on an undecaprenyl phosphate carrier lipid by a series of Tar enzymes localized around the inner face of the cytoplasmic membrane before being exported to the cell surface by a two component ATP-binding cassette (ABC) transporter system and covalently linked to PG (Brown et al., 2008; Swoboda et al., 2010; see also Physique S1). Interestingly, late actions in WTA biosynthesis in either or are essential for cell viability whereas early actions (encoded by and respectively) are not (Weidenmaier et al., 2004; D’Elia et al., 2006a; D’Elia et al., 2006b; D’Elia et al., 2009a; D’Elia et al., 2009b). Further, late stage WTA genes are in fact conditionally essential since they are dispensable in either a or deletion background; this is referred to as the essential gene paradox (D’Elia et al., 2006a; D’Elia et al., 2006b; D’Elia et al., 2009b). Two hypotheses have been given to explain these results; that toxic intermediate WTA precursors accumulate in past due GS-9350 stage WTA mutants and/or sequestration of the fundamental biosynthetic precursor, bactoprenol, takes place and this results in depletion of PG since its synthesis also needs bactoprenol being a carrier lipid (D’Elia et al., 2006b; D’Elia et al., 2009b). Walker and co-workers have lately exploited this sensation by testing for past due stage GS-9350 WTA inhibitors (WTAIs) that phenocopy the hereditary characterization from the pathway. Such.

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