Dataset Information

Adjunctive transferrin to reduce the emergence of antibiotic resistance in Gram-negative bacteria.

ABSTRACT:

Background

New strategies are needed to slow the emergence of antibiotic resistance among bacterial pathogens. In particular, society is experiencing a crisis of antibiotic-resistant infections caused by Gram-negative bacterial pathogens and novel therapeutics are desperately needed to combat such diseases. Acquisition of iron from the host is a nearly universal requirement for microbial pathogens-including Gram-negative bacteria-to cause infection. We have previously reported that apo-transferrin (lacking iron) can inhibit the growth of Staphylococcus aureus in culture and diminish emergence of resistance to rifampicin.

Objectives

To define the potential of apo-transferrin to inhibit in vitro growth of Klebsiella pneumoniae and Acinetobacter baumannii, key Gram-negative pathogens, and to reduce emergence of resistance to antibiotics.

Methods

The efficacy of apo-transferrin alone or in combination with meropenem or ciprofloxacin against K. pneumoniae and A. baumannii clinical isolates was tested by MIC assay, time-kill assay and assays for the selection of resistant mutants.

Results

We confirmed that apo-transferrin had detectable MICs for all strains tested of both pathogens. Apo-transferrin mediated an additive antimicrobial effect for both antibiotics against multiple strains in time-kill assays. Finally, adding apo-transferrin to ciprofloxacin or meropenem reduced the emergence of resistant mutants during 20?day serial passaging of both species.

Conclusions

These results suggest that apo-transferrin may have promise to suppress the emergence of antibiotic-resistant mutants when treating infections caused by Gram-negative bacteria.

SUBMITTER: Luna BM

PROVIDER: S-EPMC6736376 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Publications

Adjunctive transferrin to reduce the emergence of antibiotic resistance in Gram-negative bacteria.

Luna Brian M BM Ershova Ksenia K Yan Jun J Ulhaq Amber A Nielsen Travis B TB Hsieh Sarah S Pantapalangkoor Paul P Vanscoy Brian B Ambrose Paul P Rudin Sue S Hujer Kristine K Bonomo Robert A RA Actis Luis L Skaar Eric P EP Spellberg Brad B

The Journal of antimicrobial chemotherapy 20190901 9

<h4>Background</h4>New strategies are needed to slow the emergence of antibiotic resistance among bacterial pathogens. In particular, society is experiencing a crisis of antibiotic-resistant infections caused by Gram-negative bacterial pathogens and novel therapeutics are desperately needed to combat such diseases. Acquisition of iron from the host is a nearly universal requirement for microbial pathogens-including Gram-negative bacteria-to cause infection. We have previously reported that apo-t ...[more]

PMID: 31170282

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Project description:Background: Anaerobic 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. Methods: We 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. Results: Resistance 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. Conclusion: AGNB 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.

Project description:Phazolicin (PHZ) is a peptide antibiotic exhibiting narrow-spectrum activity against rhizobia closely related to its producer, Rhizobium sp. strain Pop5. Here, we show that the frequency of spontaneous PHZ-resistant mutants in Sinorhizobium meliloti is below the detection limit. We find that PHZ can enter S. meliloti cells through two distinct promiscuous peptide transporters, BacA and YejABEF, which belong to the SLiPT (SbmA-like peptide transporter) and ABC (ATP-binding cassette) transporter families, respectively. The dual-uptake mode explains the lack of observed resistance acquisition because the simultaneous inactivation of both transporters is necessary for resistance to PHZ. Since both BacA and YejABEF are essential for the development of functional symbiosis of S. meliloti with leguminous plants, the unlikely acquisition of PHZ resistance via the inactivation of these transporters is further disfavored. A whole-genome transposon sequencing screen did not reveal additional genes that can provide strong PHZ resistance when inactivated. However, it was found that the capsular polysaccharide KPS, the novel putative envelope polysaccharide PPP (PHZ-protecting polysaccharide), as well as the peptidoglycan layer jointly contribute to the sensitivity of S. meliloti to PHZ, most likely serving as barriers that reduce the amount of PHZ transported inside the cell. IMPORTANCE Many bacteria produce antimicrobial peptides to eliminate competitors and create an exclusive niche. These peptides act either by membrane disruption or by inhibiting essential intracellular processes. The Achilles' heel of the latter type of antimicrobials is their dependence on transporters to enter susceptible cells. Transporter inactivation results in resistance. Here, we show that a rhizobial ribosome-targeting peptide, phazolicin (PHZ), uses two different transporters, BacA and YejABEF, to enter the cells of a symbiotic bacterium, Sinorhizobium meliloti. This dual-entry mode dramatically reduces the probability of the appearance of PHZ-resistant mutants. Since these transporters are also crucial for S. meliloti symbiotic associations with host plants, their inactivation in natural settings is strongly disfavored, making PHZ an attractive lead for the development of biocontrol agents for agriculture.

Dataset Information

Adjunctive transferrin to reduce the emergence of antibiotic resistance in Gram-negative bacteria.

Background

Objectives

Methods

Results

Conclusions

Publications

Adjunctive transferrin to reduce the emergence of antibiotic resistance in Gram-negative bacteria.

Similar Datasets

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