New approach to address antibiotic resistance: Miss loading of functional membrane microdomains (FMM) of methicillin-resistant Staphylococcus aureus (MRSA)

Prasad, H.S. Nagendra; Karthik, C.S.; Manukumar, H.M.; Mallesha, L.; Mallu, P.

doi:10.1016/j.micpath.2018.11.038

Cited by 18 publications

(11 citation statements)

References 52 publications

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“…The activity of the scaffold protein flotillin with reduction of the MRSA proliferative capacity in the presence of β-lactam antibiotics has also been reported in link with perturbation of functional membrane microdomains architecture and efficient PBP2a oligomerization [ 71 , 72 ]. Lastly, other lipid domains like those mostly composed of still-unknown isoprenoid membrane lipids (e.g., staphyloxanthines) [ 73 , 74 ] could be also explored as new targets to address antibiotic resistance [ 71 , 75 ]. Because septum of the bacteria is the peculiar location of PBP, lipoteichoic acids (LTA) and cardiolipin during cell division, it could constitute an opportunity to expand the strategies to design new anti-infective agents, to overcome MRSA antibiotic resistance and to reduce the high mortality rates caused by invasive MRSA infections.…”

Section: Discussionmentioning

confidence: 99%

Effect of Ursolic and Oleanolic Acids on Lipid Membranes: Studies on MRSA and Models of Membranes

et al. 2021

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Staphylococcus aureus is an opportunistic pathogen and the major causative agent of life-threatening hospital- and community-acquired infections. A combination of antibiotics could be an opportunity to address the widespread emergence of antibiotic-resistant strains, including Methicillin-Resistant S. aureus (MRSA). We here investigated the potential synergy between ampicillin and plant-derived antibiotics (pentacyclic triterpenes, ursolic acid (UA) and oleanolic acid (OA)) towards MRSA (ATCC33591 and COL) and the mechanisms involved. We calculated the Fractional Inhibitory Concentration Index (FICI) and demonstrated synergy. We monitored fluorescence of Bodipy-TR-Cadaverin, propidium iodide and membrane potential-sensitive probe for determining the ability of UA and OA to bind to lipoteichoic acids (LTA), and to induce membrane permeabilization and depolarization, respectively. Both pentacyclic triterpenes were able to bind to LTA and to induce membrane permeabilization and depolarization in a dose-dependent fashion. These effects were not accompanied by significant changes in cellular concentration of pentacyclic triterpenes and/or ampicillin, suggesting an effect mediated through lipid membranes. We therefore focused on membranous effects induced by UA and OA, and we investigated on models of membranes, the role of specific lipids including phosphatidylglycerol and cardiolipin. The effect induced on membrane fluidity, permeability and ability to fuse were studied by determining changes in fluorescence anisotropy of DPH/generalized polarization of Laurdan, calcein release from liposomes, fluorescence dequenching of octadecyl-rhodamine B and liposome-size, respectively. Both UA and OA showed a dose-dependent effect with membrane rigidification, increase of membrane permeabilization and fusion. Except for the effect on membrane fluidity, the effect of UA was consistently higher compared with that obtained with OA, suggesting the role of methyl group position. All together the data demonstrated the potential role of compounds acting on lipid membranes for enhancing the activity of other antibiotics, like ampicillin and inducing synergy. Such combinations offer an opportunity to explore a larger antibiotic chemical space.

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Section: Discussionmentioning

confidence: 99%

Effect of Ursolic and Oleanolic Acids on Lipid Membranes: Studies on MRSA and Models of Membranes

et al. 2021

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“…MRSA-associated infections are responsible for more than 11,000 deaths annually in the United States, and globally, it is one of the leading causes of mortality and morbidity, especially in developing countries. , In addition, the World Health Organization has also included MRSA in the “serious level” among bacteria that globally threaten human health . MRSA has evolved with a broad range of strategies to overpower the defense mechanisms of the human host during colonization, causing infections that can result in death …”

Section: Introductionmentioning

confidence: 99%

“…5 MRSA has evolved with a broad range of strategies to overpower the defense mechanisms of the human host during colonization, causing infections that can result in death. 6 Most of the widely used antibiotics against MRSA were designed to block the steps involved in the biosynthesis of peptidoglycan. Peptidoglycan (PPC) is the primary component of the cell wall located outside the cytoplasmic membrane where they confer robustness and flexibility to the cell envelope.…”

Section: Introductionmentioning

confidence: 99%

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Computational Target-Based Screening of Anti-MRSA Natural Products Reveals Potential Multitarget Mechanisms of Action through Peptidoglycan Synthesis Proteins

et al. 2022

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Methicillin-resistant Staphylococcus aureus (MRSA) is one of the leading causes of bacterial infections in both healthcare and community settings. MRSA can acquire resistance to any current antibiotic, which has major implications for its current and future treatment options. As such, it is globally a major focus for infection control efforts. The mechanical rigidity provided by peptidoglycans in the bacteria cell walls makes it a promising target for broad-spectrum antibacterial drug discovery. The development of drugs that can target different stages of the synthesis of peptidoglycan in MRSA may compromise the integrity of its cell wall and consequently result in the rapid decline of diseases associated with this drug-resistant bacteria. The present study is aimed at screening natural products with known in vitro activities against MRSA to identify their potential to inhibit the proteins involved in the biosynthesis of the peptidoglycan cell wall. A total of 262 compounds were obtained when a literature survey was conducted on anti-MRSA natural products (AMNPs). Virtual screening of the AMNPs was performed against various proteins (targets) that are involved in the biosynthesis of the peptidoglycan (PPC) cell wall using Schrödinger software (release 2020–3) to determine their binding affinities. Nine AMNPs were identified as potential multitarget inhibitors against peptidoglycan biosynthesis proteins. Among these compounds, DB211 showed the strongest binding affinity and interactions with six protein targets, representing three stages of peptidoglycan biosynthesis, and thus was selected as the most promising compound. The MD simulation results for DB211 and its proteins indicated that the protein-ligand complexes were relatively stable over the simulation period of 100 ns. In conclusion, DB211 showed the potential to inhibit six proteins involved in the biosynthesis of the peptidoglycan cell wall in MRSA, thus reducing the chance of MRSA developing resistance to this compound. Therefore, DB211 provided a starting point for the design of new compounds that can inhibit multiple targets in the biosynthesis of the peptidoglycan layer in MRSA.

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“…Even then, the bacterial resistance to antibacterial drugs has increased and became a common phenomenon, which is a primary problem in a global health concern [23,24]. The possible reason lying behind the bacterial resistance could be due to evolutionary processes in antibiotic therapy namely transduction and horizontal gene transfer by conjugation [25,26]. The resistant species are known as superbugs which lead to the evolution of diseases that were controlled for a long time.…”

Section: Introductionmentioning

confidence: 99%

NiO powder synthesized through nickel metal complex degradation for water treatment

Kavitha¹,

Kumar²,

Prasad³

et al. 2019

Desalination and Water Treatment

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a b s t r a c tThis study was aimed to synthesize nickel oxide (NiO) powder and its subsequent use in bactericidal activities by exploring the role of interaction at nanoparticle-bacteria interface of E. coli (gram negative) microorganism as well as water treatment by catalysing the two toxic azo dyes reduction reactions by sodium borohydride. The NiO nanoparticles were synthesized through single-step, residue free, in situ thermal decomposition method. Their size, structural and morphological features were confirmed through various analytical tools. An average size of 7-8 nm, high crystallinity and cubic crystal structure of the synthesized nanoparticles was confirmed by XRD and HR-TEM analyses. The NiO nanoparticles revealed virtuous bactericidal activities against pathogenic E. coli. Field emission scanning electron microscopy images were used as the evidence of the cell wall deterioration. The prepared NiO nanoparticles were also used in the catalytic reduction reactions of methyl orange (MO) and congo red (CR) dyes by sodium tetra-borohydrate. The reaction rate constants for the MO and CR were 0.4989 and 0.298 min -1 , respectively. The reaction mechanism, comparison with other catalyst and recyclability of the NiO were discussed.

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New approach to address antibiotic resistance: Miss loading of functional membrane microdomains (FMM) of methicillin-resistant Staphylococcus aureus (MRSA)

Cited by 18 publications

References 52 publications

Effect of Ursolic and Oleanolic Acids on Lipid Membranes: Studies on MRSA and Models of Membranes

Effect of Ursolic and Oleanolic Acids on Lipid Membranes: Studies on MRSA and Models of Membranes

Computational Target-Based Screening of Anti-MRSA Natural Products Reveals Potential Multitarget Mechanisms of Action through Peptidoglycan Synthesis Proteins

NiO powder synthesized through nickel metal complex degradation for water treatment

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