Antimicrobial activity of the membrane-active compound nTZDpa is enhanced at low pH

Kim, Soo Min; Zou, Guijin; Kim, Hyerim; Kang, Minjeong; Ahn, Soyeon; Heo, Hee Young; Kim, Jae‐Seok; Lim, Kyung Min; Ausubel, Frederick M.; Mylonakis, Eleftherios; Gao, Huajian; Kim, Wooseong

doi:10.1016/j.biopha.2022.112977

Cited by 8 publications

(4 citation statements)

References 89 publications

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“…Membrane-active antimicrobials often exhibit bactericidal activity against MRSA biofilms and synergism with other antibiotics [ 37 , 49 ]. Thus, we hypothesized that chlorothymol targets the bacterial membrane.…”

Section: Resultsmentioning

confidence: 99%

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4-Chloro-2-Isopropyl-5-Methylphenol Exhibits Antimicrobial and Adjuvant Activity against Methicillin-Resistant Staphylococcus aureus

Kim

Lee

et al. 2022

J. Microbiol. Biotechnol.

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Methicillin-resistantStaphylococcus aureus (MRSA) causes severe infections and poses a global healthcare challenge. The utilization of novel molecules which confer synergistical effects to existing MRSA-directed antibiotics is one of the well-accepted strategies in lieu of de novo development of new antibiotics. Thymol is a key component of the essential oil of plants in the Thymus and Origanum genera. Despite the absence of antimicrobial potency, thymol is known to inhibit MRSA biofilm formation. However, the anti-MRSA activity of thymol analogs is not well characterized. Here, we assessed the antimicrobial activity of several thymol derivatives and found that 4-chloro-2-isopropyl-5-methylphenol (chlorothymol) has antimicrobial activity against MRSA and in addition it also prevents biofilm formation. Chlorothymol inhibited staphyloxanthin production, slowed MRSA motility, and altered bacterial cell density and size. This compound also showed a synergistic antimicrobial activity with oxacillin against highly resistant S. aureus clinical isolates and biofilms associated with these isolates. Our results demonstrate that chlorinated thymol derivatives should be considered as a new lead compound in anti-MRSA therapeutics.

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Section: Resultsmentioning

confidence: 99%

“…No. S7020; Invitrogen) as previously described [ 37 ]. Exponential-phase MRSA MW2 cells were washed three times with PBS and adjusted to an OD 600 of 0.5.…”

Section: Methodsmentioning

confidence: 99%

4-Chloro-2-Isopropyl-5-Methylphenol Exhibits Antimicrobial and Adjuvant Activity against Methicillin-Resistant Staphylococcus aureus

Kim

Lee

et al. 2022

J. Microbiol. Biotechnol.

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“…To determine the ATP leakage potential of the peptides, we employed a luciferase-based assay detailed in [ 32 ]. In brief, we washed the exponential phase of E. faecium strain C68 bacteria three times with PBS (pH 7.4) and adjusted it to OD 600 = 0.4 in PBS.…”

Section: Methodsmentioning

confidence: 99%

Design and Evaluation of Short Bovine Lactoferrin-Derived Antimicrobial Peptides against Multidrug-Resistant Enterococcus faecium

et al. 2022

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Enterococcus faecium has become an important drug-resistant nosocomial pathogen because of widespread antibiotic abuse. We developed short and chemically simple antimicrobial peptides (AMPs) with a selective amino acid composition, fixed charge, and hydrophobicity ratio based on the core antimicrobial motif of bovine lactoferrin (LfcinB6). Among these peptides, 5L and 6L (both 12 residues long) demonstrated a narrow spectrum and high antibacterial activity against drug-resistant E. faecium isolates with a minimal inhibitory concentration (MIC) that ranged from 4–16 µg/mL. At 32 µg/mL, peptides 5L and 6L inhibited E. faecium strain C68 biofilm formation by 90% and disrupted established biofilms by 75%. At 40 µg/mL, 5L reduced 1 × 107E. faecium persister cells by 3 logs within 120 min of exposure, whereas 6L eliminated all persister cells within 60 min. At 0.5× MIC, 5L and 6L significantly downregulated the expression of a crucial biofilm gene ace by 8 folds (p = 0.02) and 4 folds (p = 0.01), respectively. At 32 µg/mL, peptides 5L and 6L both depolarized the E. faecium membrane, increased fluidity, and eventually ruptured the membrane. Physiologically, 5L (at 8 µg/mL) altered the tricarboxylic acid cycle, glutathione, and purine metabolism. Interestingly, in an ex vivo model of porcine skin infection, compared to no treatment, 5L (at 10× MIC) effectively eliminated all 1 × 106 exponential (p = 0.0045) and persister E. faecium cells (p = 0.0002). In conclusion, the study outlines a roadmap for developing narrow-spectrum selective AMPs and presents peptide 5L as a potential therapeutic candidate to be explored against E. faecium.

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“…The ATP level was determined by using the BacTiter-GloTM Microbial Cell Viability Assay kit (Promega Corporation, Cat # G8231, Dübendorf, Switzerland) following the manufacturer’s instruction as previously described [ 55 ]. Briefly, the overnight culture was diluted 1:1000 in 5 mL LB broth and then incubated at 15 °C, 25 °C, or 37 °C with shaking (200 rpm) for 24 h. After incubation, the bacterial cultures grown at each temperature were adjusted to the same concentration.…”

Section: Methodsmentioning

confidence: 99%

Arctic Psychrotolerant Pseudomonas sp. B14-6 Exhibits Temperature-Dependent Susceptibility to Aminoglycosides

et al. 2022

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Bacteria can evade antibiotics by acquiring resistance genes, as well as switching to a non-growing dormant state without accompanying genetic modification. Bacteria in this quiescent state are called persisters, and this non-inheritable ability to withstand multiple antibiotics is referred to as antibiotic tolerance. Although all bacteria are considered to be able to form antibiotic-tolerant persisters, the antibiotic tolerance of extremophilic bacteria is poorly understood. Previously, we identified the psychrotolerant bacterium Pseudomonas sp. B14-6 from the glacier foreland of Midtre Lovénbreen in High Arctic Svalbard. Herein, we investigated the resistance and tolerance of Pseudomonas sp. B14-6 against aminoglycosides at various temperatures. This bacterium was resistant to streptomycin and susceptible to apramycin, gentamicin, kanamycin, and tobramycin. The two putative aminoglycoside phosphotransferase genes aph1 and aph2 were the most likely contributors to streptomycin resistance. Notably, unlike the mesophilic Pseudomonas aeruginosa PA14, this cold-adapted bacterium demonstrated reduced susceptibility to all tested aminoglycosides in a temperature-dependent manner. Pseudomonas sp. B14-6 at a lower temperature formed the persister cells that shows tolerance to the 100-fold minimum inhibitory concentration (MIC) of gentamicin, as well as the partially tolerant cells that withstand 25-fold MIC gentamicin. The temperature-dependent gentamicin tolerance appears to result from reduced metabolic activity. Lastly, the partially tolerant Pseudomonas sp. B14-6 cells could slowly proliferate under the bactericidal concentrations of aminoglycosides. Our results demonstrate that Pseudomonas sp. B14-6 has a characteristic ability to form cells with a range of tolerance, which appears to be inversely proportional to its growth rate.

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Antimicrobial activity of the membrane-active compound nTZDpa is enhanced at low pH

Cited by 8 publications

References 89 publications

4-Chloro-2-Isopropyl-5-Methylphenol Exhibits Antimicrobial and Adjuvant Activity against Methicillin-Resistant Staphylococcus aureus

4-Chloro-2-Isopropyl-5-Methylphenol Exhibits Antimicrobial and Adjuvant Activity against Methicillin-Resistant Staphylococcus aureus

Design and Evaluation of Short Bovine Lactoferrin-Derived Antimicrobial Peptides against Multidrug-Resistant Enterococcus faecium

Arctic Psychrotolerant Pseudomonas sp. B14-6 Exhibits Temperature-Dependent Susceptibility to Aminoglycosides

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