Organoarsenicals inhibit bacterial peptidoglycan biosynthesis by targeting the essential enzyme MurA

Garbinski, Luis D.; Rosen, Barry P.; Yoshinaga, Masafumi

doi:10.1016/j.chemosphere.2020.126911

Cited by 8 publications

(7 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A potential target of MAs(III) in bacteria is the UDP‐N‐acetylglucosamine 1‐carboxyvinyltransferase MurA (Garbinski et al, 2020), which catalyses the first committed step of bacterial peptidoglycan synthesis (Figure 5A) (Hrast et al, 2014; van Heijenoort, 2007). The genome of B. subtilis 168 carries two homologues of murA , annotated as murAA and murAB (Kock et al, 2004), whose gene products exhibit 42% identity to each other (Figure S14).…”

Section: Resultsmentioning

confidence: 99%

“…Antibiotics such as vancomycin and fosfomycin inhibit cell wall synthesis and, as a result, cause autolysis (Kahan et al, 1974; Kitano & Tomasz, 1979; Lacriola et al, 2013; Rogers & Forsberg, 1971). It has been reported that MAs(III) inhibits the in vitro activity of the UDP‐ N ‐acetylglucosamine enolpyruvyl transferase MurA from Shewanella putrefaciens 200, which catalyses the first step in the biosynthesis of cell wall peptidoglycan, although the degree of inhibition was moderate with a 40% decrease in the enzyme activity from 20 μM MAs(III) (Garbinski et al, 2020). This degree of inhibition was much smaller than the sub micromolar IC50 of MAs(III) on the growth of several Gram‐positive bacteria, suggesting that, in addition to the effect on enzyme activity, MAs(III) may also affect other processes of cell wall synthesis.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Methylarsenite is a broad‐spectrum antibiotic disrupting cell wall biosynthesis and cell membrane potential

Huang

Liu

Zhao

2022

Environmental Microbiology

View full text Add to dashboard Cite

Methylarsenite (MAs(III)), a product of arsenic biomethylation or bioreduction of methylarsenate (MAs(V)), has been proposed as a primitive antibiotic. However, the antibacterial property and the bactericidal mechanism of MAs(III) remain largely unclear. In this study, we found that MAs(III) is highly toxic to 14 strains of bacteria, especially against 9 strains of Gram-positive bacteria with half maximal inhibitory concentration (IC50) in the sub micromolar range for Staphyloccocus aureus, Microbacterium sp., Pseudarthrobacter siccitolerans and several Bacillus species. In a co-culture of B. subtilis 168 and MAs(III)-producer Enterobacter sp. CZ-1, the later reduced non-toxic MAs(V) to highly toxic MAs(III) to kill the former and gain a competitive advantage. MAs(III) induced autolysis of B. subtilis 168. Deletion of the autolysins LytC, LytD, LytE, and LytF suppressed MAs(III)-induced autolysis in B. subtilis 168. Transcriptomic analysis showed that MAs(III) downregulated the expression of the major genes involved in the biosynthesis of the cell wall peptidoglycan. Overexpression of an UDP-N-acetylglucosamine enolpyruvyl transferase gene murAA alleviated MAs(III)-induced autolysis in B. subtilis 168. MAs(III) disrupted the membrane potential of B. subtilis 168 and caused severe membrane damage. The results suggest that MAs(III) is a broadspectrum antibiotic preferentially against Gram-positive bacteria by disrupting the cell wall biosynthesis pathway and cell membrane potential.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Methylarsenite is a broad‐spectrum antibiotic disrupting cell wall biosynthesis and cell membrane potential

Huang

Liu

Zhao

2022

Environmental Microbiology

View full text Add to dashboard Cite

show abstract

“…However, one target for the antibiotic action of MAs(III) was recently identified in Shewanella putrefaciens 200 (Garbinski et al 2020 ). MAs(III), but not inorganic As(III), effectively inhibits the enzyme MurA (uridine diphosphate (UDP)- N -acetylglucosamine enolpyruvyl transferase), a cytoplasmic enzyme involved in the synthesis of the key precursor of the peptidoglycan, UDP- N -acetylmuramate (UNAM) (Barreteau et al 2008 ).…”

Section: Inorganic and Organic Arsenic-containing Drugsmentioning

confidence: 99%

“…MurA from S. putrefaciens 200 has the conserved catalytic cysteine and is sensitive to fosfomycin, while its Cys-to-Asp mutant is resistant to fosfomycin but remained sensitive to MAs(III), indicating that the two compounds have different mechanisms of action. MAs(III) represent a new area for the development of novel compounds for combating the threat of antibiotic resistance (Garbinski et al 2020 ). For MAs(III) to exert its antibiotic action, it first must enter sensitive cells.…”

Section: Inorganic and Organic Arsenic-containing Drugsmentioning

confidence: 99%

Arsenic in medicine: past, present and future

et al. 2022

Self Cite

View full text Add to dashboard Cite

Arsenicals are one of the oldest treatments for a variety of human disorders. Although infamous for its toxicity, arsenic is paradoxically a therapeutic agent that has been used since ancient times for the treatment of multiple diseases. The use of most arsenic-based drugs was abandoned with the discovery of antibiotics in the 1940s, but a few remained in use such as those for the treatment of trypanosomiasis. In the 1970s, arsenic trioxide, the active ingredient in a traditional Chinese medicine, was shown to produce dramatic remission of acute promyelocytic leukemia similar to the effect of all- trans retinoic acid. Since then, there has been a renewed interest in the clinical use of arsenicals. Here the ancient and modern medicinal uses of inorganic and organic arsenicals are reviewed. Included are antimicrobial, antiviral, antiparasitic and anticancer applications. In the face of increasing antibiotic resistance and the emergence of deadly pathogens such as the severe acute respiratory syndrome coronavirus 2, we propose revisiting arsenicals with proven efficacy to combat emerging pathogens. Current advances in science and technology can be employed to design newer arsenical drugs with high therapeutic index. These novel arsenicals can be used in combination with existing drugs or serve as valuable alternatives in the fight against cancer and emerging pathogens. The discovery of the pentavalent arsenic-containing antibiotic arsinothricin, which is effective against multidrug-resistant pathogens, illustrates the future potential of this new class of organoarsenical antibiotics.

show abstract

“…The primary mechanism of MAs(III) toxicity is due to its ability to react with protein sulfhydryl groups, thereby inhibiting enzymatic activity, DNA replication, transcription and translation (Yoshinaga‐Sakurai et al ., 2020; Li et al ., 2021; Styblo et al ., 2021). Recently MAs(III) was shown to inhibit bacterial peptidoglycan biosynthesis (Garbinski et al ., 2020). A biocycle for organoarsenicals that is parallel to the cycle for inorganic arsenic has been described (Li et al ., 2016).…”

Section: Introductionmentioning

confidence: 99%

ArsZ from Ensifer adhaerens ST2 is a novel methylarsenite oxidase

Zhang

Chen

et al. 2022

Environmental Microbiology

Self Cite

View full text Add to dashboard Cite

Summary Trivalent methylarsenite [MAs(III)] produced by biomethylation is more toxic than inorganic arsenite [As(III)]. Hence, MAs(III) has been proposed to be a primordial antibiotic. Other bacteria evolved mechanisms to detoxify MAs(III). In this study, the molecular mechanisms of MAs(III) resistance of Ensifer adhaerens ST2 were investigated. In the chromosome of E. adhaerens ST2 is a gene encoding a protein of unknown function. Here, we show that this gene, designated arsZ, encodes a novel MAs(III) oxidase that confers resistance by oxidizing highly toxic MAs(III) to relatively nontoxic MAs(V). Two other genes, arsRK, are adjacent to arsZ but are divergently encoded in the opposite direction. Heterologous expression of arsZ in Escherichia coli confers resistance to MAs(III) but not to As(III). Purified ArsZ catalyses thioredoxin‐ and NAPD+‐dependent oxidation of MAs(III). Mutational analysis of ArsZ suggests that Cys59 and Cys123 are involved in the oxidation of MAs(III). Expression of arsZ, arsR and arsK genes is induced by MAs(III) and As(III) and is likely controlled by the ArsR transcriptional repressor. These results demonstrate that ArsZ is a novel MAs(III) oxidase that contributes to E. adhaerens tolerance to environmental organoarsenicals. The arsZRK operon is widely present in bacteria within the Rhizobiaceae family.

show abstract

Organoarsenicals inhibit bacterial peptidoglycan biosynthesis by targeting the essential enzyme MurA

Cited by 8 publications

References 44 publications

Methylarsenite is a broad‐spectrum antibiotic disrupting cell wall biosynthesis and cell membrane potential

Methylarsenite is a broad‐spectrum antibiotic disrupting cell wall biosynthesis and cell membrane potential

Arsenic in medicine: past, present and future

ArsZ from Ensifer adhaerens ST2 is a novel methylarsenite oxidase

Contact Info

Product

Resources

About