Microbial synthesis of bacitracin: Recent progress, challenges, and prospects

Zhu, Jiangfeng; Wang, Shiyi; Wang, Cheng; Wang, Zhi; Luo, Guoan; Li, Junhui; Zhan, Yangyang; Cai, Dongbo; Chen, Shouwen

doi:10.1016/j.synbio.2023.03.009

Cited by 7 publications

(4 citation statements)

References 111 publications

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“…We selected a set of 10 AMPs based on recent key literature. Some AMPs were selected due to their described antimicrobial potential (e.g., cecropin P1, R8, tachyplesin I, murepavadin derivates, omiganan, and melittin), − ,, while others were included in the study because they have already been in commercial use as antibiotics (e.g., daptomycin, colistin A and B, and bacitracin A), − or because initial insights into their environmental fate have been gained (e.g., daptomycin, colistin A and B, and bacitracin A). ,, At the same time, we selected AMPs with the goal of covering a broad range of chemical diversity (i.e., linear vs cyclic peptides, different charge states, and canonical and non-canonical amino acids).…”

Section: Resultsmentioning

confidence: 99%

Hydrolysis of Antimicrobial Peptides by Extracellular Peptidases in Wastewater

Wichmann,

Gruseck,

Zumstein

2023

Environ. Sci. Technol.

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Several antimicrobial peptides (AMPs) are emerging as promising novel antibiotics. When released into wastewater streams after use, AMPs might be hydrolyzed and inactivated by wastewater peptidasesresulting in a reduced release of active antimicrobials into wastewater-receiving environments. A key step towards a better understanding of the fate of AMPs in wastewater systems is to investigate the activity and specificity of wastewater peptidases. Here, we quantified peptidase activity in extracellular extracts from different stages throughout the wastewater treatment process. For all four tested municipal wastewater treatment plants, we detected highest activity in raw wastewater. Complementarily, we assessed the potential of enzymes in raw wastewater extracts to biotransform 10 selected AMPs. We found large variations in the susceptibility of AMPs to enzymatic transformation, indicating substantial substrate specificity of extracted enzymes. To obtain insights into peptidase specificities, we searched for hydrolysis products of rapidly biotransformed AMPs and quantified selected products using synthetic standards. We found that hydrolysis occurred at specific sites and that these sites were remarkably conserved across the four tested wastewaters. Together, these findings provide insights into the fate of AMPs in wastewater systems and can inform the selection and design of peptide-based antibiotics that are hydrolyzable by wastewater peptidases.

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Section: Resultsmentioning

confidence: 99%

Hydrolysis of Antimicrobial Peptides by Extracellular Peptidases in Wastewater

Wichmann,

Gruseck,

Zumstein

2023

Environ. Sci. Technol.

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“…Here, we demonstrate that the ytpAB operon contributes to the high level of intrinsic bacitracin resistance characteristic of B. subtilis. Bacitracin is a cyclic dodecapeptide metalloantibiotic produced by some B. licheniformis and B. subtilis species (70). Bacitracin binds together with a Zn 2+ ion to sequester the pyrophosphate moiety and first prenyl group of the UPP carrier lipid released on the outer leaflet of the membrane following the transglycosylation reaction (29).…”

Section: Discussionmentioning

confidence: 99%

TheBacillus subtiliscell envelope stress-inducibleytpABoperon modulates membrane properties and contributes to bacitracin resistance

Willdigg,

Patel,

Arquilevich

et al. 2024

Preprint

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Antibiotics that inhibit peptidoglycan synthesis trigger the activation of both specific and general protective responses. σMresponds to diverse antibiotics that inhibit cell wall synthesis. Here, we demonstrate that cell wall inhibiting drugs, such as bacitracin and cefuroxime, induce the σM-dependentytpABoperon. YtpA is a predicted hydrolase previously proposed to generate the putative lysophospholipid antibiotic bacilysocin (lysophosphatidylglycerol), and YtpB is the branchpoint enzyme for the synthesis of membrane-localized C35terpenoids. Using targeted lipidomics we reveal that YtpA is not required for the production of lysophosphatidylglycerol. Nevertheless,ytpAwas critical for growth in a mutant strain defective for homeoviscous adaptation due to a lack of genes for the synthesis of branched chain fatty acids and the Des phospholipid desaturase. Consistently, overexpression ofytpAincreased membrane fluidity as monitored by fluorescence anisotropy. TheytpAgene contributes to bacitracin resistance in mutants additionally lacking thebceABorbcrCgenes, which directly mediate bacitracin resistance. These epistatic interactions support a model in which σM-dependent induction of theytpABoperon helps cells tolerate bacitracin stress, either by facilitating the flipping of the undecaprenyl-phosphate carrier lipid or by impacting the assembly or function of membrane-associated complexes proteins involved in cell wall homeostasis.

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“…Bacillus licheniformis is another industrial workhorse that has been used for decades for the production of amylase 104 and the synthesis of bacitracin for veterinary applications. 105 The strain has similar characteristics as B. subtilis, but is particularly superior under anaerobic conditions. Several B. licheniformis strains have been isolated from oil reservoirs and have therefore adapted to oxygen-limiting conditions and higher temperatures.…”

Section: Bgc Expression In Other Bacillus Speciesmentioning

confidence: 99%