Targeting Pan-Resistant Bacteria With Antibodies to a Broadly Conserved Surface Polysaccharide Expressed During Infection

Skurnik, David; Davis, Michael R.; Benedetti, Dennis; Moravec, K; Cywes‐Bentley, Colette; Roux, Damien; Traficante, David C.; Walsh, Rebecca L.; Maira-Litrán, Tomas; Cassidy, Sara K. B.; Hermos, Christina; Martin, Thomas R.; Thakkallapalli, Erin L.; Vargas, Sara O.; McAdam, Alexander J.; Lieberman, Tami D.; Kishony, Roy; LiPuma, John J.; Pier, Gerald B.; Goldberg, Joanna B.; Priebe, Gregory P.

doi:10.1093/infdis/jis254

Cited by 52 publications

(43 citation statements)

References 30 publications

(49 reference statements)

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“…While previous studies have shown that bacterial capsules can be effective immunogens, this is the first set of data to our knowledge that supports the potential use of the capsular polysaccharide as a target for antibody-mediated therapeutics in A. baumannii. Additional targets which may also be useful include OmpA (23) and the noncapsular bacterial surface polysaccharide poly-␤-(1-6)-N-acetylglucosamine (52).…”

Section: Discussionmentioning

confidence: 99%

The K1 Capsular Polysaccharide from Acinetobacter baumannii Is a Potential Therapeutic Target via Passive Immunization

et al. 2013

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fThe emergence of extremely resistant and panresistant Gram-negative bacilli, such as Acinetobacter baumannii, requires consideration of nonantimicrobial therapeutic approaches. The goal of this report was to evaluate the K1 capsular polysaccharide from A. baumannii as a passive immunization target. Its structure was determined by a combination of mass spectrometric and nuclear magnetic resonance (NMR) techniques. Molecular mimics that might raise the concern for autoimmune disease were not identified. Immunization of CD1 mice demonstrated that the K1 capsule is immunogenic. The monoclonal antibody (MAb) 13D6, which is directed against the K1 capsule from A. baumannii, was used to determine the seroprevalence of the K1 capsule in a collection of 100 A. baumannii strains. Thirteen percent of the A. baumannii isolates from this collection were seroreactive to MAb 13D6. Opsonization of K1-positive strains, but not K1-negative strains, with MAb 13D6 significantly increased neutrophil-mediated bactericidal activity in vitro (P < 0.05). Lastly, treatment with MAb 13D6 3 and 24 h after bacterial challenge in a rat soft tissue infection model resulted in a significant decrease in the growth/survival of a K1-positive strain compared to that of a K1-negative strain or to treatment with a vehicle control (P < 0.0001). These data support the proof of principle that the K1 capsule is a potential therapeutic target via passive immunization. Other serotypes require assessment, and pragmatic challenges exist, such as the need to serotype infecting strains and utilize serotype-specific therapy. Nonetheless, this approach may become an important therapeutic option with increasing antimicrobial resistance and a diminishing number of active antimicrobials.

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Section: Discussionmentioning

confidence: 99%

The K1 Capsular Polysaccharide from Acinetobacter baumannii Is a Potential Therapeutic Target via Passive Immunization

et al. 2013

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“…The RNDs play a major role in the intrinsic multidrug resistance phenotypes of both A. baumannii and P. aeruginosa (6,19,20). To test our hypothesis that intrinsic and acquired antibiotic resistance enhances fitness during infection, in other clinically relevant organisms, we assessed the fitness of Tn insertions in the A1S_1649 and A1S_1801 genes prepared in a highly virulent A. baumannii strain AB5075 (21) using a murine model of lethality after intraperitoneal challenge (22). As expected, mutations in both genes led to increased susceptibility to antibiotics, with the MIC for tobramycin decreasing from 48 mg/liter for AB5075 wild type to 12 and 16 mg/liter for AB5075 with Tn insertions in homologs of A1S_1649 and A1S_1801, respectively.…”

Section: Fitness Cost Of Antibiotic Susceptibility In Other Pathogenimentioning

confidence: 99%

Fitness cost of antibiotic susceptibility during bacterial infection

et al. 2015

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Advances in high-throughput DNA sequencing allow for a comprehensive analysis of bacterial genes that contribute to virulence in a specific infectious setting. Such information can yield new insights that affect decisions on how to best manage major public health issues such as the threat posed by increasing antimicrobial drug resistance. Much of the focus has been on the consequences of the selective advantage conferred on drug-resistant strains during antibiotic therapy. It is thought that the genetic and phenotypic changes that confer resistance also result in concomitant reductions in in vivo fitness, virulence, and transmission. However, experimental validation of this accepted paradigm is modest. Using a saturated transposon library of Pseudomonas aeruginosa, we identified genes across many functional categories and operons that contributed to maximal in vivo fitness during lung infections in animal models. Genes that bestowed both intrinsic and acquired antibiotic resistance provided a positive in vivo fitness advantage to P. aeruginosa during infection. We confirmed these findings in the pathogenic bacteria Acinetobacter baumannii and Vibrio cholerae using murine and rabbit infection models, respectively. Our results show that efforts to confront the worldwide increase in antibiotic resistance might be exacerbated by fitness advantages that enhance virulence in drug-resistant microbes.

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“…In Acinetobacter baumannii , deletion of the pga locus led to loss of the biofilm phenotype, which was restored by complementation [23]. Similar findings were found with Burkholderia cepacia complex (BCC) [24], K. pneumoniae [25], and Bordetella pertussis [26]. Recently, PNAG’s role in biofilm formation was reported in Bacillus subtilis [27], the first Gram-positive bacillus found to produce PNAG.…”

Section: Biology Of Pnagmentioning

confidence: 68%

“…The presence of pga genes is not enough, by itself, to firmly establish that the PNAG molecule is synthesized and expressed. Nonetheless, it is notable that, to date, essentially all the investigations finding pga genes in a microbe’s chromosome were able to confirm the presence of PNAG at the bacterial surface[6,22–24,26,33,34]. Interestingly, the introduction of the pga locus into a PNAG-negative bacteria can lead to the production of PNAG [27].…”

Section: Genetics and Biosynthesis Of Pnagmentioning

confidence: 99%

The exceptionally broad-based potential of active and passive vaccination targeting the conserved microbial surface polysaccharide PNAG

Skurnik

Cywes‐Bentley

Pier

2016

Expert Review of Vaccines

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Summary A challenging component of vaccine development is the large serologic diversity of protective antigens. Remarkably, there is a conserved surface/capsular polysaccharide, one of the most effective vaccine targets, expressed by a large number of bacterial, fungal and eukaryotic pathogens: poly-N-acetyl glucosamine (PNAG). Natural antibodies to PNAG are poorly effective at mediating in vitro microbial killing or in vivo protection. Removing most of the acetate substituents to produce a deacetylated glycoform, or using synthetic oligosaccharides of poly-β-1-6-linked glucosamine conjugated to carrier proteins, results in vaccines that elicit high levels of broad-based immunity. A fully human monoclonal antibody is highly active in laboratory and preclinical studies and has been successfully tested in a phase-I setting. Both the synthetic oligosaccharide conjugate vaccine and MAb will be further tested in humans starting in 2016; but, even if effective against only a fraction of the PNAG-producing pathogens, a major advance in vaccine-preventable diseases will occur.

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Targeting Pan-Resistant Bacteria With Antibodies to a Broadly Conserved Surface Polysaccharide Expressed During Infection

Abstract: Our findings raise potential new therapeutic options against PNAG-producing bacteria, including even pan-resistant pathogens.

Cited by 52 publications

References 30 publications

The K1 Capsular Polysaccharide from Acinetobacter baumannii Is a Potential Therapeutic Target via Passive Immunization

The K1 Capsular Polysaccharide from Acinetobacter baumannii Is a Potential Therapeutic Target via Passive Immunization

Fitness cost of antibiotic susceptibility during bacterial infection

The exceptionally broad-based potential of active and passive vaccination targeting the conserved microbial surface polysaccharide PNAG

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