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Antibiotic class with potent in vivo activity targeting lipopolysaccharide synthesis in Gram-negative bacteria.

ABSTRACT: Here, we describe the identification of an antibiotic class acting via LpxH, a clinically unexploited target in lipopolysaccharide synthesis. The lipopolysaccharide synthesis pathway is essential in most Gram-negative bacteria and there is no analogous pathway in humans. Based on a series of phenotypic screens, we identified a hit targeting this pathway that had activity on efflux-defective strains of Escherichia coli. We recognized common structural elements between this hit and a previously published inhibitor, also with activity against efflux-deficient bacteria. With the help of X-ray structures, this information was used to design inhibitors with activity on efflux-proficient, wild-type strains. Optimization of properties such as solubility, metabolic stability and serum protein binding resulted in compounds having potent in vivo efficacy against bloodstream infections caused by the critical Gram-negative pathogens E. coli and Klebsiella pneumoniae. Other favorable properties of the series include a lack of pre-existing resistance in clinical isolates, and no loss of activity against strains expressing extended-spectrum-β-lactamase, metallo-β-lactamase, or carbapenemase-resistance genes. Further development of this class of antibiotics could make an important contribution to the ongoing struggle against antibiotic resistance.

SUBMITTER: Huseby DL

PROVIDER: S-EPMC11009625 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature

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Antibiotic class with potent in vivo activity targeting lipopolysaccharide synthesis in Gram-negative bacteria.

Huseby Douglas L DL Cao Sha S Zamaratski Edouard E Sooriyaarachchi Sanjeewani S Ahmad Shabbir S Bergfors Terese T Krasnova Laura L Pelss Juris J Ikaunieks Martins M Loza Einars E Katkevics Martins M Bobileva Olga O Cirule Helena H Gukalova Baiba B Grinberga Solveiga S Backlund Maria M Simoff Ivailo I Leber Anna T AT Berruga-Fernández Talía T Antonov Dmitry D Konda Vivekananda R VR Lindström Stefan S Olanders Gustav G Brandt Peter P Baranczewski Pawel P Vingsbo Lundberg Carina C Liepinsh Edgars E Suna Edgars E Jones T Alwyn TA Mowbray Sherry L SL Hughes Diarmaid D Karlén Anders A

Proceedings of the National Academy of Sciences of the United States of America 20240405 15

Here, we describe the identification of an antibiotic class acting via LpxH, a clinically unexploited target in lipopolysaccharide synthesis. The lipopolysaccharide synthesis pathway is essential in most Gram-negative bacteria and there is no analogous pathway in humans. Based on a series of phenotypic screens, we identified a hit targeting this pathway that had activity on efflux-defective strains of <i>Escherichia coli</i>. We recognized common structural elements between this hit and a previo ...[more]

PMID: 38579010

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Project description:BackgroundAnaerobic Gram-negative bacteria (AGNB) play a significant role as both pathogens and essential members of the human microbiota. Despite their clinical importance, there remains limited understanding regarding their antimicrobial resistance (AMR) patterns. This knowledge gap poses challenges in effectively managing AGNB-associated infections, as empirical treatment approaches may not adequately address the evolving resistance landscape. To bridge this research gap, we conducted a comprehensive study aimed at exploring the role of human AGNB as a reservoir of AMR. This can provide valuable insights for the prevention and management of anaerobic infections.MethodsWe studied the prevalence of AMR and AMR determinants conferring resistance to metronidazole (nimE), imipenem (cfiA), piperacillin-tazobactam (cepA), cefoxitin (cfxA), clindamycin (ermF), chloramphenicol (cat) and mobile genetic elements (MGEs) such as cfiAIS and IS1186 associated with the cfiA and nim gene expression. These parameters were studied in Bacteroides spp., Fusobacterium spp., Prevotella spp., Veillonella spp., Sutterella spp., and other clinical AGNB.ResultsResistance to metronidazole, clindamycin, imipenem, piperacillin-tazobactam, cefoxitin and chloramphenicol was 29%, 33.5%, 0.5%, 27.5%, 26.5% and 0%, respectively. The presence of resistance genes, viz., nim, ermF, cfiA, cepA, cfxA, was detected in 24%, 33.5%, 10%, 9.5%, 21.5% isolates, respectively. None of the tested isolates showed the presence of a cat gene and MGEs, viz., cfiAIS and IS1186. The highest resistance to all antimicrobial agents was exhibited by Bacteroides spp. The association between resistant phenotypes and genotypes was complete in clindamycin, as all clindamycin-resistant isolates showed the presence of ermF gene, and none of the susceptible strains harbored this gene; similarly, all isolates were chloramphenicol-susceptible and also lacked the cat gene, whereas the association was low among imipenem and piperacillin-tazobactam. Metronidazole and imipenem resistance was seen to be dependent on insertion sequences for the expression of AMR genes. A constrained co-existence of cepA and cfiA gene in B. fragilis species was seen. Based on the absence and presence of the cfiA gene, we divided B. fragilis into two categories, Division I (72.6%) and Division II (27.3%), respectively.ConclusionAGNB acts as a reservoir of specific AMR genes, which may pose a threat to other anaerobes due to functional compatibility and acquisition of these genes. Thus, AST-complying standard guidelines must be performed periodically to monitor the local and institutional susceptibility trends, and rational therapeutic strategies must be adopted to direct empirical management.

Dataset Information

Antibiotic class with potent in vivo activity targeting lipopolysaccharide synthesis in Gram-negative bacteria.

Publications

Antibiotic class with potent in vivo activity targeting lipopolysaccharide synthesis in Gram-negative bacteria.

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