High susceptibility of MDR and XDR Gram-negative pathogens to biphenyl-diacetylene-based difluoromethyl-<i>allo</i>-threonyl-hydroxamate LpxC inhibitors

Titécat, Marie; Liang, Xiaofei; Lee, Chul‐Jin; Charlet, Audrey; Hocquet, Didier; Lambert, Thierry; Pages, Jean-Marie; Courcol, René; Sebbane, Florent; Toone, Eric J.; Zhou, Pei; Lemaître, Nadine

doi:10.1093/jac/dkw210

Cited by 27 publications

(28 citation statements)

References 27 publications

(23 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Therefore, proteins involved in lipid A synthesis, such as LpxC, have been identified as targets to inhibit lipid A biosynthesis (6). Inhibitors are being developed as antimicrobial agents, and some showed promising antibacterial activity against Gramnegative species, including Pseudomonas aeruginosa, Escherichia coli, and Klebsiella pneumoniae, while exhibiting poor in vitro activity against A. baumannii (31). However, LpxC inhibitors have a positive influence on A. baumannii clearance in vivo, as they increase cell permeability, increasing antibiotic susceptibility (7,9).…”

Section: Discussionmentioning

confidence: 99%

Dual Role of gnaA in Antibiotic Resistance and Virulence in Acinetobacter baumannii

Chen

Yan

et al. 2019

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Acinetobacter baumannii is an important Gram-negative pathogen in hospital-related infections. However, treatment options for A. baumannii infections have become limited due to multidrug resistance. Bacterial virulence is often associated with capsule genes found in the K locus, many of which are essential for biosynthesis of the bacterial envelope. However, the roles of other genes in the K locus remain largely unknown. From an in vitro evolution experiment, we obtained an isolate of the virulent and multidrug-resistant A. baumannii strain MDR-ZJ06, called MDR-ZJ06M, which has an insertion by the ISAba16 transposon in gnaA (encoding UDP-N-acetylglucosamine C-6 dehydrogenase), a gene found in the K locus. The isolate showed an increased resistance toward tigecycline, whereas the MIC decreased in the case of carbapenems, cephalosporins, colistin, and minocycline. By using knockout and complementation experiments, we demonstrated that gnaA is important for the synthesis of lipooligosaccharide and capsular polysaccharide and that disruption of the gene affects the morphology, drug susceptibility, and virulence of the pathogen.

show abstract

Section: Discussionmentioning

confidence: 99%

Dual Role of gnaA in Antibiotic Resistance and Virulence in Acinetobacter baumannii

Chen

Yan

et al. 2019

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…Molecules designed to disrupt Gram-negative OM stability are being investigated, and show great promise as a therapeutic strategy [50]. In particular, targeting the Mla pathway could be an interesting pharmacological target as it is conserved amongst all Gram-negative bacteria [18] and therefore offers the potential for broad-spectrum activity and clinical utility.…”

Section: Discussionmentioning

confidence: 99%

The Mla pathway is critical for Pseudomonas aeruginosa resistance to outer membrane permeabilization and host innate immune clearance

et al. 2017

View full text Add to dashboard Cite

Pseudomonas aeruginosa is an important opportunistic pathogen that has become a serious problem due to increased rates of antibiotic resistance. Due to this along with a dearth in novel antibiotic development, especially against Gram-negative pathogens, new therapeutic strategies are needed to prevent a post-antibiotic era. Here we describe the importance of the vacJ/Mla pathway in resisting bactericidal actions of the host innate immune response. P. aeruginosa tn5 transposon mutants in genes from the VacJ/Mla pathway showed increased susceptibility to killing by the host cathelicidin antimicrobial peptide, LL-37 when compared to the wild-type parent strain. The P. aeruginosa vacJ− mutant demonstrated increased membrane permeability upon damage as well as sensitivity to killing in the presence of the detergent sodium dodecyl sulfate and the divalent cation chelator EDTA. When exposed to human whole blood and serum complement, the vacJ− mutant was killed more rapidly when compared to the wild-type parent strain and complemented mutant. Finally, in an in vivo mouse lung infection model, infection with the vacJ− mutant resulted in reduced mortality, lower bacterial burden, and reduced lung damage when compared to the wild-type strain. This study highlights the potential in therapeutically targeting the VacJ/Mla pathway in sensitizing P. aeruginosa to killing by the host innate immune response.

show abstract

“…The most promising among them is LpxC, a zinc-dependent deacetylase. Inhibition of LpxC increases the antibiotic susceptibility of A. baumannii (107), including XDR clinical isolates (108). The MIC 50/90 values of a new LpxC inhibitor were 0.8/3.2 g/ml (MIC range, 0.5 to Ն64 g/ml) when tested on 25 clinical A. baumannii isolates, including 19 MDR/XDR strains (7 OXA-23 producers and 1 OXA-40 producer) (109).…”

Section: New Therapeutic Optionsmentioning

confidence: 99%

New Treatment Options against Carbapenem-Resistant Acinetobacter baumannii Infections

Isler¹,

Doi

Bonomo

et al. 2019

Antimicrob Agents Chemother

256

179

View full text Add to dashboard Cite

Carbapenem-resistantAcinetobacter baumannii(CRAB) is a perilous nosocomial pathogen causing substantial morbidity and mortality. Current treatment options for CRAB are limited and suffer from pharmacokinetic limitations, such as high toxicity and low plasma levels. As a result, CRAB is declared as the top priority pathogen by the World Health Organization for the investment in new drugs. This urgent need for new therapies, in combination with faster FDA approval process, accelerated new drug development and placed several drug candidates in the pipeline. This article reviews available information about the new drugs and other therapeutic options focusing on agents in clinical or late-stage preclinical studies for the treatment of CRAB, and it evaluates their expected benefits and potential shortcomings.

show abstract

High susceptibility of MDR and XDR Gram-negative pathogens to biphenyl-diacetylene-based difluoromethyl-allo-threonyl-hydroxamate LpxC inhibitors

Abstract: These in vitro data highlight the therapeutic potential of the new LpxC inhibitor LPC-058 against MDR/XDR strains and set the stage for subsequent in vivo studies.

Cited by 27 publications

References 27 publications

Dual Role of gnaA in Antibiotic Resistance and Virulence in Acinetobacter baumannii

Dual Role of gnaA in Antibiotic Resistance and Virulence in Acinetobacter baumannii

The Mla pathway is critical for Pseudomonas aeruginosa resistance to outer membrane permeabilization and host innate immune clearance

New Treatment Options against Carbapenem-Resistant Acinetobacter baumannii Infections

Contact Info

Product

Resources

About