Antibacterial Activity of Small Molecules Which Eradicate Methicillin-Resistant Staphylococcus aureus Persisters
The serious challenge posed by multidrug-resistant bacterial infections with concomitant treatment failure and high mortality rates presents an urgent threat to the global health. We herein report the discovery of a new class of potent antimicrobial compounds that are highly effective against Gram-p...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-02-01
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| Series: | Frontiers in Microbiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmicb.2022.823394/full |
| _version_ | 1818939634590154752 |
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| author | Mohamad Hamad Mohamad Hamad Farah Al-Marzooq Farah Al-Marzooq Vunnam Srinivasulu Hany A. Omar Hany A. Omar Ashna Sulaiman Dana M. Zaher Gorka Orive Taleb H. Al-Tel Taleb H. Al-Tel |
| author_facet | Mohamad Hamad Mohamad Hamad Farah Al-Marzooq Farah Al-Marzooq Vunnam Srinivasulu Hany A. Omar Hany A. Omar Ashna Sulaiman Dana M. Zaher Gorka Orive Taleb H. Al-Tel Taleb H. Al-Tel |
| author_sort | Mohamad Hamad |
| collection | DOAJ |
| description | The serious challenge posed by multidrug-resistant bacterial infections with concomitant treatment failure and high mortality rates presents an urgent threat to the global health. We herein report the discovery of a new class of potent antimicrobial compounds that are highly effective against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). The compounds were efficiently synthesized in one-pot employing a cascade of Groebke–Blackburn–Bienaymé and aza-Michael addition reactions. Phenotypic screening of the pilot library against various bacterial species including methicillin-sensitive and MRSA strains, has identified potent chemotypes with minimal inhibitory concentrations (MIC) of 3.125–6.25 μg/ml. The most potent compounds were fast-acting at eradicating exponentially growing MRSA, with killing achieved after 30 min of exposure to the compounds. They were also able to kill MRSA persister cells which are tolerant to most available medications. Microscopic analysis using fluorescence microscope and atomic force microscope indicate that these compounds lead to disruption of bacterial cell envelopes. Most notably, bacterial resistance toward these compounds was not observed after 20 serial passages in stark contrast to the significant resistance developed rapidly upon exposure to a clinically relevant antibiotic. Furthermore, the compounds did not induce significant hemolysis to human red blood cells. In vivo safety studies revealed a high safety profile of these motifs. These small molecules hold a promise for further studies and development as new antibacterial agents against MRSA infections. |
| first_indexed | 2024-12-20T06:26:52Z |
| format | Article |
| id | doaj.art-7f129298a38a496eb174152c924993b8 |
| institution | Directory Open Access Journal |
| issn | 1664-302X |
| language | English |
| last_indexed | 2024-12-20T06:26:52Z |
| publishDate | 2022-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Microbiology |
| spelling | doaj.art-7f129298a38a496eb174152c924993b82022-12-21T19:50:16ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2022-02-011310.3389/fmicb.2022.823394823394Antibacterial Activity of Small Molecules Which Eradicate Methicillin-Resistant Staphylococcus aureus PersistersMohamad Hamad0Mohamad Hamad1Farah Al-Marzooq2Farah Al-Marzooq3Vunnam Srinivasulu4Hany A. Omar5Hany A. Omar6Ashna Sulaiman7Dana M. Zaher8Gorka Orive9Taleb H. Al-Tel10Taleb H. Al-Tel11Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab EmiratesCollege of Health Sciences, University of Sharjah, Sharjah, United Arab EmiratesSharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab EmiratesCollege of Medicine and Health Sciences, UAE University, Al Ain, United Arab EmiratesSharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab EmiratesSharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab EmiratesCollege of Pharmacy, University of Sharjah, Sharjah, United Arab EmiratesSharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab EmiratesSharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab EmiratesNanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Bilbao, SpainSharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab EmiratesCollege of Pharmacy, University of Sharjah, Sharjah, United Arab EmiratesThe serious challenge posed by multidrug-resistant bacterial infections with concomitant treatment failure and high mortality rates presents an urgent threat to the global health. We herein report the discovery of a new class of potent antimicrobial compounds that are highly effective against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). The compounds were efficiently synthesized in one-pot employing a cascade of Groebke–Blackburn–Bienaymé and aza-Michael addition reactions. Phenotypic screening of the pilot library against various bacterial species including methicillin-sensitive and MRSA strains, has identified potent chemotypes with minimal inhibitory concentrations (MIC) of 3.125–6.25 μg/ml. The most potent compounds were fast-acting at eradicating exponentially growing MRSA, with killing achieved after 30 min of exposure to the compounds. They were also able to kill MRSA persister cells which are tolerant to most available medications. Microscopic analysis using fluorescence microscope and atomic force microscope indicate that these compounds lead to disruption of bacterial cell envelopes. Most notably, bacterial resistance toward these compounds was not observed after 20 serial passages in stark contrast to the significant resistance developed rapidly upon exposure to a clinically relevant antibiotic. Furthermore, the compounds did not induce significant hemolysis to human red blood cells. In vivo safety studies revealed a high safety profile of these motifs. These small molecules hold a promise for further studies and development as new antibacterial agents against MRSA infections.https://www.frontiersin.org/articles/10.3389/fmicb.2022.823394/fullbacterial resistanceantibacterialMRSApersistersmulti-drug resistanceStaphylococcus aureus |
| spellingShingle | Mohamad Hamad Mohamad Hamad Farah Al-Marzooq Farah Al-Marzooq Vunnam Srinivasulu Hany A. Omar Hany A. Omar Ashna Sulaiman Dana M. Zaher Gorka Orive Taleb H. Al-Tel Taleb H. Al-Tel Antibacterial Activity of Small Molecules Which Eradicate Methicillin-Resistant Staphylococcus aureus Persisters Frontiers in Microbiology bacterial resistance antibacterial MRSA persisters multi-drug resistance Staphylococcus aureus |
| title | Antibacterial Activity of Small Molecules Which Eradicate Methicillin-Resistant Staphylococcus aureus Persisters |
| title_full | Antibacterial Activity of Small Molecules Which Eradicate Methicillin-Resistant Staphylococcus aureus Persisters |
| title_fullStr | Antibacterial Activity of Small Molecules Which Eradicate Methicillin-Resistant Staphylococcus aureus Persisters |
| title_full_unstemmed | Antibacterial Activity of Small Molecules Which Eradicate Methicillin-Resistant Staphylococcus aureus Persisters |
| title_short | Antibacterial Activity of Small Molecules Which Eradicate Methicillin-Resistant Staphylococcus aureus Persisters |
| title_sort | antibacterial activity of small molecules which eradicate methicillin resistant staphylococcus aureus persisters |
| topic | bacterial resistance antibacterial MRSA persisters multi-drug resistance Staphylococcus aureus |
| url | https://www.frontiersin.org/articles/10.3389/fmicb.2022.823394/full |
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