DNA Binding Ligands Targeting Drug-Resistant Bacteria:  Structure, Activity, and Pharmacology

Kaizerman, Jacob A.; Gross, Matthew; Ge, Yigong; White, S.W.; Hu, Wenhao; Duan, Jian‐Xin; Baird, Eldon E.; Johnson, Kirk W.; Tanaka, Richard D.; Moser, Heinz; Bürli, Roland W.

doi:10.1021/jm030097a

Cited by 67 publications

(60 citation statements)

References 28 publications

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“…Therefore, it is likely that the DNA binding activity of the bis-indoles is a major component of the mechanism of action of these compounds. The proposed mechanism for the bis-indoles is thus consistent with that of other classes of DNA binding antibacterial agents (37). While the inhibition of DNA and RNA synthesis constitutes a well-established cellular consequence of treatment with a DNA binding agent, the potent inhibition of the other MMS pathways, particularly cell wall synthesis, suggests that there may be additional mechanisms of action, or that the inhibition of cell wall synthesis is a secondary effect.…”

Section: As It Was Too Weak) These Values Indi-supporting

confidence: 73%

DNA Targeting as a Likely Mechanism Underlying the Antibacterial Activity of Synthetic Bis-Indole Antibiotics

Opperman

Kwasny

et al. 2016

Antimicrob Agents Chemother

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bWe previously reported the synthesis and biological activity of a series of cationic bis-indoles with potent, broad-spectrum antibacterial properties. Here, we describe mechanism of action studies to test the hypothesis that these compounds bind to DNA and that this target plays an important role in their antibacterial outcome. The results reported here indicate that the bis-indoles bind selectively to DNA at A/T-rich sites, which is correlated with the inhibition of DNA and RNA synthesis in representative Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli) organisms. Further, exposure of E. coli and S. aureus to representative bis-indoles resulted in induction of the DNA damage-inducible SOS response. In addition, the bis-indoles were found to be potent inhibitors of cell wall biosynthesis; however, they do not induce the cell wall stress stimulon in S. aureus, suggesting that this pathway is inhibited by an indirect mechanism. In light of these findings, the most likely basis for the observed activities of these compounds is their ability to bind to the minor groove of DNA, resulting in the inhibition of DNA and RNA synthesis and other secondary effects.

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Section: As It Was Too Weak) These Values Indi-supporting

confidence: 73%

DNA Targeting as a Likely Mechanism Underlying the Antibacterial Activity of Synthetic Bis-Indole Antibiotics

Opperman

Kwasny

et al. 2016

Antimicrob Agents Chemother

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“…Although optimization of polyamide architecture and functionalization will be necessary to promote organism-specific uptake in S. aureus, these results suggest a future approach for targeted disruption of antibiotic resistance transfer. Minorgroove binders similar to Py-Im polyamides have shown activity against S. aureus in vitro and in animal models of infection (31,32). Interestingly, there is a natural precedent for targeting NES activity as a means to limit DNA transfer, in the form of a functional CRISPR containing a nes-specific spacer that is present in the genome of Staphylococcus epidermidis strain RP62a (33).…”

Section: Discussionmentioning

confidence: 99%

Molecular basis of antibiotic multiresistance transfer in Staphylococcus aureus

Edwards¹,

Betts²,

Frazier³

et al. 2013

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

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Multidrug-resistant Staphylococcus aureus infections pose a significant threat to human health. Antibiotic resistance is most commonly propagated by conjugative plasmids like pLW1043, the first vancomycin-resistant S. aureus vector identified in humans. We present the molecular basis for resistance transmission by the nicking enzyme in S. aureus (NES), which is essential for conjugative transfer. NES initiates and terminates the transfer of plasmids that variously confer resistance to a range of drugs, including vancomycin, gentamicin, and mupirocin. The NES N-terminal relaxase-DNA complex crystal structure reveals unique protein-DNA contacts essential in vitro and for conjugation in S. aureus. Using this structural information, we designed a DNA minor groove-targeted polyamide that inhibits NES with low micromolar efficacy. The crystal structure of the 341-residue C-terminal region outlines a unique architecture; in vitro and cell-based studies further establish that it is essential for conjugation and regulates the activity of the N-terminal relaxase. This conclusion is supported by a smallangle X-ray scattering structure of a full-length, 665-residue NES-DNA complex. Together, these data reveal the structural basis for antibiotic multiresistance acquisition by S. aureus and suggest novel strategies for therapeutic intervention.A ntibiotic resistance, which arises in bacterial pathogens through conjugative plasmid DNA transfer, is a well-established threat to global health. For example, whereas vancomycin has been essential in treating recalcitrant Staphylococcus aureus infections for decades, vancomycin-resistant S. aureus (VRSA) strains have now appeared in clinical settings worldwide (1-3). VRSA first arose in the United States through the interplay of conjugative DNA transfer and resistance-determinant transposition. The resulting plasmid, pLW1043, has been sequenced and contains not only a vanHAX vancomycin-resistance transposon, but also a cadre of putative DNA transfer genes (4). It was recently shown that the S. aureus plasmid pSK41, which is closely related to pLW1043, mediates the transfer of vancomycin resistance from Enterococcus faecalis into strains of methicillin resistant S. aureus (MRSA) (5). Conjugative bacterial plasmids use almost exclusively plasmid-encoded factors that work in concert to coordinate the cell-to-cell transfer of one strand of the duplex plasmid (6, 7). An element common to all conjugative processes is the plasmid-encoded relaxase enzyme that initiates and terminates transfer by creating a transient single-strand DNA break and covalent protein-DNA intermediate (8,9).The vancomycin-resistance plasmid pLW1043 (4) and related plasmids from S. aureus (10, 11), including pSK41 and pGO1 (12-14) as well as plasmids from streptococcal, lactococcal, and clostridial strains, encode a relaxase enzyme termed nicking enzyme in Staphylococcus (NES) that exhibits a unique fulllength sequence (Fig. S1). It is 665 residues in length, confines its relaxase motifs to its N-terminal ∼220 aa, an...

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“…We will further refer to them as single-ribbon ligands. Research efforts in this area have focused on the improvement of the anticancer, [14][15][16][17][18] antibacterial, [19][20][21][22][23] antiprotozoal, [11,24,25] or antifungal [25][26][27] action. On the other hand, there is the group of double-ribbon minor groove binders, which comprise pyrrolic polyamides that actually dimerize in the minor groove as well as hairpin structures, in which two polyamides are covalently connected.…”

Section: Introductionmentioning

confidence: 99%

Sequence‐Specific Positions of Water Molecules at the Interface between DNA and Minor Groove Binders

Spitzer¹,

Fuchs²,

Markt³

et al. 2008

ChemPhysChem

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Ligands able to specifically recognize DNA sequences are of fundamental interest as transcription-controlling drugs. Herein, we analyze the positions of water molecules relative to B-DNA base pairs in the minor groove of X-ray and NMR protein data bank (PDB) structures. The patterns observed for water molecules at the interface between DNA and a ligand are compared with those obtained for structures without a ligand. Although the ligand end groups are often charged, and therefore highly hydrated, they do not alter the water patterns, which show considerable differences for the AT and CG base pairs. For AT they are much more precise than for CG in both ligand-containing and ligand-free structures. This behavior strongly indicates that the release of water molecules upon ligand binding leads to a gain of entropy and explains why this effect is especially pronounced for A-tract B-DNA sequences.

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DNA Binding Ligands Targeting Drug-Resistant Bacteria: Structure, Activity, and Pharmacology

Cited by 67 publications

References 28 publications

DNA Targeting as a Likely Mechanism Underlying the Antibacterial Activity of Synthetic Bis-Indole Antibiotics

DNA Targeting as a Likely Mechanism Underlying the Antibacterial Activity of Synthetic Bis-Indole Antibiotics

Molecular basis of antibiotic multiresistance transfer in Staphylococcus aureus

Sequence‐Specific Positions of Water Molecules at the Interface between DNA and Minor Groove Binders

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