Cephalosporin-Glycopeptide Combinations for Use against Clinical Methicillin-Resistant Staphylococcus aureus Isolates: Enhanced In vitro Antibacterial Activity

Tang, Hung Jen; Lai, Chih Cheng; Chen, Chi Chung; Zhang, Chun Cheng; Weng, Tzu Chieh; Yu, Wen Liang; Chen, Hung-Jui; Chiu, Yu Hsin; Ko, Wen Chien; Chuang, Yin Ching

doi:10.3389/fmicb.2017.00884

Cited by 13 publications

(7 citation statements)

References 34 publications

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“…2a,b ). Among these latter, we confirmed the strong and previously reported synergy between two widely used antibiotics for S. aureus , cefepime and teicoplanin 27 , 28 , and validated it against several MRSA (methicillin-resistant S. aureus ) clinical isolates belonging to worldwide prevalent clonal complexes and different infection sources (Supplementary Table 1 ), including a strain resistant to the last-resort antibiotic tigecycline (Fig. 2d and Supplementary Information ).…”

Section: Resultssupporting

confidence: 84%

Systematic analysis of drug combinations against Gram-positive bacteria

Cacace,

Kim,

Varik

et al. 2023

Nat Microbiol

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Drug combinations can expand options for antibacterial therapies but have not been systematically tested in Gram-positive species. We profiled ~8,000 combinations of 65 antibacterial drugs against the model species Bacillus subtilis and two prominent pathogens, Staphylococcus aureus and Streptococcus pneumoniae. Thereby, we recapitulated previously known drug interactions, but also identified ten times more novel interactions in the pathogen S. aureus, including 150 synergies. We showed that two synergies were equally effective against multidrug-resistant S. aureus clinical isolates in vitro and in vivo. Interactions were largely species-specific and synergies were distinct from those of Gram-negative species, owing to cell surface and drug uptake differences. We also tested 2,728 combinations of 44 commonly prescribed non-antibiotic drugs with 62 drugs with antibacterial activity against S. aureus and identified numerous antagonisms that might compromise the efficacy of antimicrobial therapies. We identified even more synergies and showed that the anti-aggregant ticagrelor synergized with cationic antibiotics by modifying the surface charge of S. aureus. All data can be browsed in an interactive interface (https://apps.embl.de/combact/).

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Section: Resultssupporting

confidence: 84%

Systematic analysis of drug combinations against Gram-positive bacteria

Cacace,

Kim,

Varik

et al. 2023

Nat Microbiol

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“…2a-b ). Among these latter, we confirmed the known synergy between cefepime and teicoplanin 24, 25 , and we validated it against several MRSA (Methicillin-Resistant S. aureus ) clinical isolates, including a strain resistant to the last-resort antibiotic tigecycline ( Fig. 2d, Extended Data Fig.…”

Section: Resultssupporting

confidence: 61%

High-throughput profiling of drug interactions in Gram-positive bacteria

Cacace¹,

Kim²,

Knopp³

et al. 2022

Preprint

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Drug combinations present a powerful strategy to tackle antimicrobial resistance, but have not been systematically tested in many bacterial species. Here, we used an automated high-throughput setup to profile ~ 8000 combinations between 65 antibacterial drugs in three Gram-positive species: the model species, Bacillus subtilis and two prominent pathogens, Staphylococcus aureus and Streptococcus pneumoniae. Thereby, we recapitulate previously known drug interactions, but also identify ten times more interactions than previously reported in the pathogen S. aureus, including two synergies that were also effective in multi-drug resistant clinical S. aureus isolates in vitro and in vivo. Interactions were largely species-specific and mostly synergistic for drugs targeting the same cellular process, as observed also for Gram-negative species1. Yet, the dominating synergies are clearly distinct between Gram-negative and Gram-positive species, and are driven by different bottlenecks in drug uptake and vulnerabilities of their cell surface structures. To further explore interactions of commonly prescribed non-antibiotic drugs with antibiotics, we tested 2728 of such combinations in S. aureus, detecting a plethora of unexpected antagonisms that could compromise the efficacy of antimicrobial treatments in the age of polypharmacy. We uncovered even more synergies than antagonisms, some of which we could demonstrate as effective combinations in vivo against multi-drug resistant clinical isolates. Among them, we showed that the antiaggregant ticagrelor interferes with purine metabolism and changes the surface charge of S. aureus, leading to strong synergies with cationic antibiotics. Overall, this exemplifies the untapped potential of approved non-antibacterial drugs to be repurposed as antibiotic adjuvants. All data can be browsed through an interactive interface (https://apps.embl.de/combact/).

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“…All experiments were performed in duplicate. The statistical signi cances were compared with that of each drug alone and no drug control: * P < 0.05, ** P < 0.01, and *** P < 0.001 [15].…”

Section: Combination Killing Methodsmentioning

confidence: 99%

Synergistic effect of repurposed mitomycin C in combination with antibiotics against Aeromonas infection: in vitro and in vivo studies.

Yeh,

Chen,

Lai

et al. 2024

Preprint

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Background Aeromonas infections pose a significant threat, presenting a potentially life-threatening condition associated with high mortality rates. This study investigates the potential of mitomycin C (MMC), an anticancer drug, as a novel antimicrobial agent against Aeromonas infections. Methods The minimum inhibitory concentrations (MICs) of MMC and antibiotics against clinical isolates of Aeromonas species were assessed, using broth microdilution. Synergistic effects of MMC with antibiotics were assessed through time-kill studies. Additionally, we analyzed MMC's intracellular killing effects using a representative Aeromonas isolate. Efficacy of combined therapies was evaluated in neutropenic mice model. Results We found that only three antibiotics-ciprofloxacin (CIP), levofloxacin (LVX), and tigecycline (TGC) maintained susceptibility rates exceeding 90% under high inoculum conditions. Significantly, in vitro investigations demonstrated a synergistic effect over a 24-hour period when combining the 1/8x MIC of MMC with the 1x or 1/2x MICs of LVX, in a time–kill study. Furthermore, in vivo in neutropenic mice, the combination of 2 mg/kg and 1 mg/kg MMC with LVX resulted in 100% and 80% survival, respectively, whereas treatment with either drug alone resulted in 0% survival rate. Conclusions These findings suggest that MMC can be repurposed as an antimicrobial agent, particularly with a minimized dose and in combination with antibiotics.

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Cephalosporin-Glycopeptide Combinations for Use against Clinical Methicillin-Resistant Staphylococcus aureus Isolates: Enhanced In vitro Antibacterial Activity

Cited by 13 publications

References 34 publications

Systematic analysis of drug combinations against Gram-positive bacteria

Systematic analysis of drug combinations against Gram-positive bacteria

High-throughput profiling of drug interactions in Gram-positive bacteria

Synergistic effect of repurposed mitomycin C in combination with antibiotics against Aeromonas infection: in vitro and in vivo studies.

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