Antibacterial drug leads targeting isoprenoid biosynthesis

Zhu, Wei; Zhang, Yonghui; Sinko, William; Hensler, Mary E.; Olson, Joshua; Molohon, Katie J.; Lindert, Steffen; Cao, Rong; Li, Kai; Wang, Ke; Wang, Yan; Liu, Yi Liang; Sankovsky, Anna; Oliveira, César Augusto F. de; Mitchell, Douglas A.; Nizet, Victor; McCammon, J. Andrew; Oldfield, Eric

doi:10.1073/pnas.1219899110

Cited by 92 publications

(170 citation statements)

References 31 publications

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“…In recent work, we (49) and others (50, 51) identified several anionic, bacterial cell growth inhibitors that, in addition to inhibiting bacteria-specific enzyme targets, might have activity as uncouplers, as expected for lipophilic, weak acid, classic uncouplers like CCCP and DNP. We first investigated seven compounds with known antibacterial activity and a diverse range of proposed protein targets.…”

Section: Resultsmentioning

confidence: 55%

Antiinfectives targeting enzymes and the proton motive force

Feng

Zhu

Schurig-Briccio

et al. 2015

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

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148

169

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There is a growing need for new antibiotics. Compounds that target the proton motive force (PMF), uncouplers, represent one possible class of compounds that might be developed because they are already used to treat parasitic infections, and there is interest in their use for the treatment of other diseases, such as diabetes. Here, we tested a series of compounds, most with known antiinfective activity, for uncoupler activity. Many cationic amphiphiles tested positive, and some targeted isoprenoid biosynthesis or affected lipid bilayer structure. As an example, we found that clomiphene, a recently discovered undecaprenyl diphosphate synthase inhibitor active against Staphylococcus aureus, is an uncoupler. Using in silico screening, we then found that the anti-glioblastoma multiforme drug lead vacquinol is an inhibitor of Mycobacterium tuberculosis tuberculosinyl adenosine synthase, as well as being an uncoupler. Because vacquinol is also an inhibitor of M. tuberculosis cell growth, we used similarity searches based on the vacquinol structure, finding analogs with potent (∼0.5-2 μg/mL) activity against M. tuberculosis and S. aureus. Our results give a logical explanation of the observation that most new tuberculosis drug leads discovered by phenotypic screens and genome sequencing are highly lipophilic (logP ∼5.7) bases with membrane targets because such species are expected to partition into hydrophobic membranes, inhibiting membrane proteins, in addition to collapsing the PMF. This multiple targeting is expected to be of importance in overcoming the development of drug resistance because targeting membrane physical properties is expected to be less susceptible to the development of resistance.T here is a need for new antibiotics, due to the increase in drug resistance (1, 2). For example, some studies report that by 2050, absent major improvements in drug discovery and use, more individuals will die from drug-resistant bacterial infections than from cancer, resulting in a cumulative effect on global gross domestic product of as much as 100 trillion dollars (3, 4). To discover new drugs, new targets, leads, concepts, and implementations are needed (5, 6).Currently, one major cause of death from bacterial infections is tuberculosis (TB) (7), where very highly drug-resistant strains have been found (8). Therapy is lengthy, even with drug-sensitive strains, and requires combination therapies with four drugs. Two recent TB drugs/drug leads (9-11) are TMC207 [bedaquiline (1); Sirturo] and SQ109 (2) (Fig. 1). Bedaquiline (1) targets the Mycobacterium tuberculosis ATP synthase (9) whereas SQ109 (2) has been proposed to target MmpL3 (mycobacterial membrane protein large 3), a trehalose monomycolate transporter essential for cell wall biosynthesis (12). SQ109 (2) is a lipophilic base containing an adamantyl "headgroup" connected via an ethylene diamine "linker" to a geranyl (C 10 ) "side chain," and in recent work (13), we synthesized a series of 11 analogs of SQ109 (2) finding that the ethanolamine (3) was more potent th...

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Section: Resultsmentioning

confidence: 55%

Antiinfectives targeting enzymes and the proton motive force

Feng

Zhu

Schurig-Briccio

et al. 2015

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

Self Cite

148

169

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“…Recently, several studies have shown that bacterial UPPS is an attractive antibiotic target (4,88) and that inhibitors of UPPS are protective in a mouse model of infection (89). Based on the experimental data concerning G. lamblia cis-PT and phylogenetic analysis of cis-PT from Trypanosoma sp., Leishmania sp., and Plasmodium sp., we predict that targeting protozoan cis-PT may also be a reasonable strategy to treat and control infections such as malaria, sleeping sickness, Chagas disease, leishmaniasis, and intestinal infections.…”

Section: Genetic Validation Of Two-component Ngbr/hcit Complex In Humansmentioning

confidence: 99%

cis-Prenyltransferase: New Insights into Protein Glycosylation, Rubber Synthesis, and Human Diseases

Grabińska

Park

Sessa

2016

Journal of Biological Chemistry

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cis-Prenyltransferases (cis-PTs) constitute a large family of enzymes conserved during evolution and present in all domains of life. cis-PTs catalyze consecutive condensation reactions of allylic diphosphate acceptor with isopentenyl diphosphate (IPP) in the cis (Z) configuration to generate linear polyprenyl diphosphate. The chain lengths of isoprenoid carbon skeletons vary widely from neryl pyrophosphate (C 10 ) to natural rubber (C >10,000 ). The homo-dimeric bacterial enzyme, undecaprenyl diphosphate synthase (UPPS), has been structurally and mechanistically characterized in great detail and serves as a model for understanding the mode of action of eukaryotic cis-PTs. However, recent experiments have revealed that mammals, fungal, and long-chain plant cis-PTs are heteromeric enzymes composed of two distantly related subunits. In this review, the classification, function, and evolution of cis-PTs will be discussed with a special emphasis on the role of the newly described NgBR/Nus1 subunit and its plants' orthologs as essential, structural components of the cis-PTs activity.

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“…Four subsequent steps lead to the synthesis of IPP and DMAPP, the universal precursors to FPP. The synthesis of undecaprenyl pyrophosphate in bacteria originates from all-trans-FPP by the addition of eight isopentenyl units catalysed by the soluble enzyme undecaprenyl pyrophosphate synthase UppS (Guo et al, 2005;Teng & Liang, 2012a, b;Zhu et al, 2013). Undecaprenyl pyrophosphate and dolichol de novo synthesis are distinguished by terminal products (an isoprenyl pyrophosphate versus an alcohol) as well as the saturation state of the a-isoprene units (unsaturated versus saturated).…”

Section: Biosynthesis Of the Eubacterial Undecaprenyl Lipid Carriersmentioning

confidence: 99%

Conservation of the PTEN catalytic motif in the bacterial undecaprenyl pyrophosphate phosphatase, BacA/UppP

Bickford

Nick

2013

Microbiology

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Isoprenoid lipid carriers are essential in protein glycosylation and bacterial cell envelope biosynthesis. The enzymes involved in their metabolism (synthases, kinases and phosphatases) are therefore critical to cell viability. In this review, we focus on two broad groups of isoprenoid pyrophosphate phosphatases. One group, containing phosphatidic acid phosphatase motifs, includes the eukaryotic dolichyl pyrophosphate phosphatases and proposed recycling bacterial undecaprenol pyrophosphate phosphatases, PgpB, YbjB and YeiU/LpxT. The second group comprises the bacterial undecaprenol pyrophosphate phosphatase, BacA/UppP, responsible for initial formation of undecaprenyl phosphate, which we predict contains a tyrosine phosphate phosphatase motif resembling that of the tumour suppressor, phosphatase and tensin homologue (PTEN). Based on protein sequence alignments across species and 2D structure predictions, we propose catalytic and lipid recognition motifs unique to BacA/UppP enzymes. The verification of our proposed active-site residues would provide new strategies for the development of substratespecific inhibitors which mimic both the lipid and pyrophosphate moieties, leading to the development of novel antimicrobial agents.

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Antibacterial drug leads targeting isoprenoid biosynthesis

Cited by 92 publications

References 31 publications

Antiinfectives targeting enzymes and the proton motive force

Antiinfectives targeting enzymes and the proton motive force

cis-Prenyltransferase: New Insights into Protein Glycosylation, Rubber Synthesis, and Human Diseases

Conservation of the PTEN catalytic motif in the bacterial undecaprenyl pyrophosphate phosphatase, BacA/UppP

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