Challenges of Antibacterial Discovery

Silver, Lynn L.

doi:10.1128/cmr.00030-10

Cited by 1,110 publications

(996 citation statements)

References 386 publications

(360 reference statements)

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“…The 4462, 4497, 6078, and 7578 antibodies were iodinated using the Iodogen method (ThermoFisher). Protein A-deficient S. aureus USA300 bacteria, cultured on tryptic soy agar with 5% defibrinated blood at 37°C for 20 h, were washed with PBS, fixed with 2% paraformaldehyde in PBS, washed again and resuspended at 8 × 10 5 CFU/mL in PBS.…”

Section: Methodsmentioning

confidence: 99%

“…5 The recent increase in MDR infections has revitalized interest in antibody-based approaches to antibiotic discovery, 6 with molecules targeting both Gram-positive and Gram-negative pathogens an active area of discovery. The use of animal serum containing antibodies that target bacterial antigens was a common therapeutic approach pre-dating the development of small molecule antibiotics, 7 but technological advances in antibody discovery, including B-cell cloning from human patients, 8 has invigorated research into monoclonal antibody (mAb)-based antibiotics.…”

Section: Introductionmentioning

confidence: 99%

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Structural investigation of humanS. aureus-targeting antibodies that bind wall teichoic acid

Fong¹,

Kajihara²,

Chen³

et al. 2018

mAbs

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Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are a growing health threat worldwide. Efforts to identify novel antibodies that target S. aureus cell surface antigens are a promising direction in the development of antibiotics that can halt MRSA infection. We biochemically and structurally characterized three patient-derived MRSA-targeting antibodies that bind to wall teichoic acid (WTA), which is a polyanionic surface glycopolymer. In S. aureus, WTA exists in both α- and β-forms, based on the stereochemistry of attachment of a N-acetylglucosamine residue to the repeating phosphoribitol sugar unit. We identified a panel of antibodies cloned from human patients that specifically recognize the α or β form of WTA, and can bind with high affinity to pathogenic wild-type strains of S. aureus bacteria. To investigate how the β-WTA specific antibodies interact with their target epitope, we determined the X-ray crystal structures of the three β-WTA specific antibodies, 4462, 4497, and 6078 (Protein Data Bank IDs 6DWI, 6DWA, and 6DW2, respectively), bound to a synthetic WTA epitope. These structures reveal that all three of these antibodies, while utilizing distinct antibody complementarity-determining region sequences and conformations to interact with β-WTA, fulfill two recognition principles: binding to the β-GlcNAc pyranose core and triangulation of WTA phosphate residues with polar contacts. These studies reveal the molecular basis for targeting a unique S. aureus cell surface epitope and highlight the power of human patient-based antibody discovery techniques for finding novel pathogen-targeting therapeutics.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Structural investigation of humanS. aureus-targeting antibodies that bind wall teichoic acid

Fong¹,

Kajihara²,

Chen³

et al. 2018

mAbs

View full text Add to dashboard Cite

show abstract

“…The "golden age" of antimicrobial breakthrough lasted 60 years from the discovery of penicillin in 1928 and supplied the large majority of the drugs in current use [1]. However, bacteria naturally develop resistance, and contributory factors include: the limited number of therapeutic targets that antimicrobials act on; the greater need due to the demands of modern medicine and aging populations; their misuse and overuse; most importantly, the failure to find new antimicrobials to restock the pipeline [2].…”

Section: Introductionmentioning

confidence: 99%

Interaction between a cationic bolaamphiphile and DNA: The route towards nanovectors for oligonucleotide antimicrobials

Mamusa

Resta

Barbero³

et al. 2016

Colloids and Surfaces B: Biointerfaces

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“…Thus, there is a great need to develop new mechanisms by which Gramnegative antibacterial agents can combat bacterial antibiotic resistance. 3,4 One of the emerging targets in Gram-negative bacteria is LpxC, an essential enzyme in the lipid A biosynthetic pathway. Because LpxC does not show homology to any mammalian protein, it is a promising antibiotic target for developing novel therapeutics against multidrug-resistant Gram-negative pathogens.…”

mentioning

confidence: 99%

LpxC Inhibitors: Design, Synthesis, and Biological Evaluation of Oxazolidinones as Gram-negative Antibacterial Agents

Kurasaki¹,

Tsuda²,

Shinoyama³

et al. 2016

ACS Med. Chem. Lett.

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Herein we report a scaffold-hopping approach to identify a new scaffold with a zinc binding headgroup. Structural information was used to give novel oxazolidinone-based LpxC inhibitors. In particular, the most potent compound, 23j, showed a low efflux ratio, nanomolar potencies against E. coli LpxC enzyme, and excellent antibacterial activity against E. coli and K. pneumoniae. Computational docking was used to predict the interaction between 23j and E. coli LpxC, suggesting that the interactions with C207 and C63 contribute to the strong activity. These results provide new insights into the design of next-generation LpxC inhibitors.KEYWORDS: Antibacterial, Gram-negative bacteria, LpxC, scaffold hopping, oxazolidinone I n recent years, infections caused by antibiotic-resistant bacteria have emerged as major threats to human communities worldwide. 1 However, the late-stage clinical development pipeline for antibacterials has been unacceptably lean in recent decades. 2 In particular, no drugs have reached advanced stages of development for the treatment of infection due to multidrug-resistant Gram-negative bacteria. Thus, there is a great need to develop new mechanisms by which Gramnegative antibacterial agents can combat bacterial antibiotic resistance. 3,4 One of the emerging targets in Gram-negative bacteria is LpxC, an essential enzyme in the lipid A biosynthetic pathway. Because LpxC does not show homology to any mammalian protein, it is a promising antibiotic target for developing novel therapeutics against multidrug-resistant Gram-negative pathogens. 5 LpxC inhibitors have drawn much attention in new entities for Gram-negative antibacterial agents. 6 To date, extensive investigations have been carried out on the mechanism underlying the LpxC enzyme. 7,8 Those studies have identified a zinc ion to catalyze deacetylation and a hydrophobic tunnel binding a myristate fatty acyl chain of the natural substrate. Merck researchers discovered 1 (L-161,240) containing an oxazoline scaffold in the mid-1990s, 6 and recently several LpxC inhibitors have been reported as antibacterial agents, 9−17 although to our knowledge none have reached the market yet.Among the well-characterized compounds, threonyl-hydroxamate derivatives are representative LpxC inhibitors, such as 2 (CHIR-090) and 3 (LPC-009) (Figure 1a). 18,19 According to a few reports on the binding modes of these compounds, the threonyl-hydroxamate group of 2 and that of 3 occupy the active site, and its diphenyl acetylene or phenyl-diyne group penetrates the hydrophobic passage. 19−21 Herein we report a scaffold hopping approach to identify a new scaffold with a zinc-binding headgroup. Additionally, we describe the synthesis, biological evaluation, and docking analysis of oxazolidinone-based LpxC inhibitors. Among these compounds, 23j showed remarkable antibacterial activity.

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Challenges of Antibacterial Discovery

Cited by 1,110 publications

References 386 publications

Structural investigation of humanS. aureus-targeting antibodies that bind wall teichoic acid

Structural investigation of humanS. aureus-targeting antibodies that bind wall teichoic acid

Interaction between a cationic bolaamphiphile and DNA: The route towards nanovectors for oligonucleotide antimicrobials

LpxC Inhibitors: Design, Synthesis, and Biological Evaluation of Oxazolidinones as Gram-negative Antibacterial Agents

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