Small molecule inhibitor of lipoteichoic acid synthesis is an antibiotic for Gram-positive bacteria

Richter, Stefan; Elli, Derek; Kim, Hwan Keun; Hendrickx, Antoni P. A.; Sorg, Joseph A.; Schneewind, Olaf; Missiakas, Dominique

doi:10.1073/pnas.1217337110

Cited by 96 publications

(133 citation statements)

References 42 publications

(51 reference statements)

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“…Gram-positive bacteria with three ltaS homologues (Clostridium perfringens) or four ltaS homologues (B. cereus and B. anthracis) were also susceptible to compound 1771-mediated growth inhibition (107). Scanning and thin-section transmission electron microscopy of bacterial cultures treated with subinhibitory concentrations of 1771 revealed dispersal of bacterial cluster or chain formation, increases in cell size, deformation of cell surface and shape, thickening, and structural disorganization of the cell wall envelope (107). Thus, LTA synthesis, but not WTA, may be essential for growth in several different Gram-positive bacteria and chemical inhibition may be used to assess the presence of LtaS enzymes and type I LTA in less-well-characterized organisms.…”

Section: Teichoic Acids and Bacterial Growthmentioning

confidence: 99%

“…Compound 1771 inhibited the growth of antibiotic-resistant methicillin-resistant S. aureus (MRSA), including USA300 LAC, and VRE, i.e., vancomycin-resistant Enterococcus faecalis and E. faecium, whose genomes harbor two ltaS homologues. Gram-positive bacteria with three ltaS homologues (Clostridium perfringens) or four ltaS homologues (B. cereus and B. anthracis) were also susceptible to compound 1771-mediated growth inhibition (107). Scanning and thin-section transmission electron microscopy of bacterial cultures treated with subinhibitory concentrations of 1771 revealed dispersal of bacterial cluster or chain formation, increases in cell size, deformation of cell surface and shape, thickening, and structural disorganization of the cell wall envelope (107).…”

Section: Teichoic Acids and Bacterial Growthmentioning

confidence: 99%

“…Reduced ltaS expression or chemical inhibition of the ltaS gene product results in severe cell division defects, a phenotype that is exacerbated when staphylococci are grown under conditions above 30°C (64,78,107). Some organisms carry more than one ltaS-like gene.…”

Section: Teichoic Acids and Bacterial Growthmentioning

confidence: 99%

“…Deletion of the two ltaS genes in L. monocytogenes reduced bacterial plating efficiency by more than 6-log (81,(84)(85)(86). By screening a library of 167,405 compounds for inhibition of S. aureus growth at 42°C, compound 1771 was identified as an inhibitor of LTA synthesis (107). The spectrum of antibiotic activity for compound 1771 was analyzed against several Gram-positive bacteria harboring poly(Gro-P) LTA as well as LtaS homologues.…”

Section: Teichoic Acids and Bacterial Growthmentioning

confidence: 99%

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Lipoteichoic Acids, Phosphate-Containing Polymers in the Envelope of Gram-Positive Bacteria

2014

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Section: Teichoic Acids and Bacterial Growthmentioning

confidence: 99%

Section: Teichoic Acids and Bacterial Growthmentioning

confidence: 99%

Section: Teichoic Acids and Bacterial Growthmentioning

confidence: 99%

Section: Teichoic Acids and Bacterial Growthmentioning

confidence: 99%

See 2 more Smart Citations

Lipoteichoic Acids, Phosphate-Containing Polymers in the Envelope of Gram-Positive Bacteria

2014

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“…7.). Recently, renewed interest, albeit still fragmentary, in the modification of TA has been observed, in view of the functional importance of (glycosylated) TAs (for example, in the search for new antimicrobials [237]) and technical advances in analyses. The biosynthesis of the WTA of B. subtilis 168 is initiated by the priming TagO glycosyltransferase (GT), which transfers an N-acetylglucosamine (GlcNAc) residue to an undecaprenyl phosphate (UndP) carrier.…”

Section: Fig 6 O-antigen Lps Biosynthesis and Lps Assembly And Transpmentioning

confidence: 99%

The Sweet Tooth of Bacteria: Common Themes in Bacterial Glycoconjugates

Tytgat

Lebeer

2014

Microbiol Mol Biol Rev

128

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SUMMARY Humans have been increasingly recognized as being superorganisms, living in close contact with a microbiota on all their mucosal surfaces. However, most studies on the human microbiota have focused on gaining comprehensive insights into the composition of the microbiota under different health conditions (e.g., enterotypes), while there is also a need for detailed knowledge of the different molecules that mediate interactions with the host. Glycoconjugates are an interesting class of molecules for detailed studies, as they form a strain-specific barcode on the surface of bacteria, mediating specific interactions with the host. Strikingly, most glycoconjugates are synthesized by similar biosynthesis mechanisms. Bacteria can produce their major glycoconjugates by using a sequential or an en bloc mechanism, with both mechanistic options coexisting in many species for different macromolecules. In this review, these common themes are conceptualized and illustrated for all major classes of known bacterial glycoconjugates, with a special focus on the rather recently emergent field of glycosylated proteins. We describe the biosynthesis and importance of glycoconjugates in both pathogenic and beneficial bacteria and in both Gram-positive and -negative organisms. The focus lies on microorganisms important for human physiology. In addition, the potential for a better knowledge of bacterial glycoconjugates in the emerging field of glycoengineering and other perspectives is discussed.

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Antibacterial Small Molecules That Potently Inhibit Staphylococcus aureus Lipoteichoic Acid Biosynthesis

et al. 2019

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The rise of antibiotic resistance, especially in Staphylococcus aureus,and the increasing deathrate due to multiresistant bacteria have been well documented. The need for new chemical entitiesa nd/or the identification of novel targets for antibacterial drug development is high. Lipoteichoic acid (LTA), am embrane-attached anionic polymer,i si mportant for the growth and virulence of many Gram-positive bacteria, and interest has been high in the discovery of LTAb iosynthesis inhibitors. Thus far,o nly ah andfulo fL TA biosynthesis inhibitors have been described with moderate( MIC = 5.34 mgmL À1 )t ol ow (MIC = 1024 mgmL À1 )a ctivities against S. aureus. Herein we describe the identification of novel compounds that potently inhibit LTA biosynthesis in S. aureus,d isplaying impressive antibacterial activities (MIC as low as 0.25 mgmL À1 )a gainst methicillin-resistant S. aureus (MRSA). Under similari nvitro assay conditions, these compounds are 4-fold more potent than vancomycin and 8fold more potent than linezolid against MRSA.

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Small molecule inhibitor of lipoteichoic acid synthesis is an antibiotic for Gram-positive bacteria

Cited by 96 publications

References 42 publications

Lipoteichoic Acids, Phosphate-Containing Polymers in the Envelope of Gram-Positive Bacteria

Lipoteichoic Acids, Phosphate-Containing Polymers in the Envelope of Gram-Positive Bacteria

The Sweet Tooth of Bacteria: Common Themes in Bacterial Glycoconjugates

Antibacterial Small Molecules That Potently Inhibit Staphylococcus aureus Lipoteichoic Acid Biosynthesis

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