Bactericidal Synergism Between Antibiotics and Phage Endolysin Cpl-711 to kill Multidrug-Resistant Pneumococcus

Letrado, Patricia; Corsini, Bruno; Díez-Martínez, Roberto; Bustamante, Noemí; Yuste, José; García, Pedro

doi:10.2217/fmb-2018-0077

Cited by 50 publications

(28 citation statements)

References 21 publications

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“…Bacteria were grown at 37°C to stationary phase at a final concentration of ≈ 10 8 CFU/ml, taking samples after 2, 4 and 7 h of incubation. As in previous works (Rodríguez-Cerrato et al, 2007a; Letrado et al, 2018), incubation time was no further prolonged due to S. pneumoniae autolysis. Serial dilutions of samples were cultured onto blood agar plates for viable cell titer determination.…”

Section: Methodssupporting

confidence: 77%

“…Phage lysins represent a new generation of antimicrobials that have several advantages over conventional antibiotics: (1) they are very fast in their lethal activity, practically upon contact with the bacteria; (2) in general, they are very specific to the pathogen, which allows to preserve the normal microbiota; (3) the appearance of resistant mutants seems very unlikely, probably because the peptidoglycan is an essential and well-conserved structural component that cannot be easily modified without compromising their fitness (Pastagia et al, 2013, and the references therein). The intrinsic killing activity of phage lysins can even be improved by engineering the wild type enzymes (São-José, 2018) and/or combining them with other lysins, antibiotics or certain compounds to get a synergistic effect (Letrado et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…These chimeras, Cpl-711 and PL3, showed an increased bactericidal and therapeutic activity with respect to their parental enzymes (Díez-Martínez et al, 2013; Blázquez et al, 2016; Corsini et al, 2018). It is noteworthy that antipneumococcal lysins have demonstrated synergy with a variety of antibiotics (Rodríguez-Cerrato et al, 2007a; Vouillamoz et al, 2013; Letrado et al, 2018), and also displayed a synergistic effect when they catalyze the breakage of different peptidoglycan bonds. This is the case of Cpl-1 lysozyme and Pal or LytA NAM-amidases (Jado et al, 2003; Loeffler and Fischetti, 2003; Rodríguez-Cerrato et al, 2007a; Domenech et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Synergy Between Two Chimeric Lysins to Kill Streptococcus pneumoniae

Vázquez

Garcı́a

2019

Front. Microbiol.

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Phage lysins constitute a new generation of antimicrobials that are becoming a promising alternative and complementation to current antibiotic therapies, which are nowadays called into question by the increasing numbers of multiresistant bacteria. Streptococcus pneumoniae is a leading human pathogen causing serious infectious diseases in children and adults. Within the host-parasite interplay system of pneumococcus and its phages, several antipneumococcal lysins have been described and, among them, chimeric lysins Cpl-711 and PL3 stand out for their potent bactericidal activities. Here, evidence is presented on the synergistic cooperation of the catalytically diverse lysins Cpl-711 and PL3 in different assays, like purified cell wall enzymatic degradation, in vitro bacterial cell growth inhibition, and killing of both planktonic and biofilm grown cells. Synergy between Cpl-711 and PL3 has been shown to reduce the amount of enzyme necessary to inhibit growth in checkerboard assays with a sum of fractional inhibitory concentrations ≤0.5 for all pneumococcal strains tested, while also significatively increasing bactericidal effect by ≥2 logs with respect to the sum of activities of Cpl-711 and PL3 individual treatments. Moreover, the combination of these two lysins showed synergy in an adult zebrafish model of pneumococcal infection. This study consolidates the possibility of formulating highly efficient and synergistic antibacterial enzymes that could improve our ability to fight multiresistant bacterial infections.

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Section: Methodssupporting

confidence: 77%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Synergy Between Two Chimeric Lysins to Kill Streptococcus pneumoniae

Vázquez

Garcı́a

2019

Front. Microbiol.

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“…The finding that Pf suppresses phagocytosis contrasts with reports that lytic phages promote phagocytosis and interact synergistically with phagocytes (152)(153)(154)(155)(156). There are also suggestions that some species of phage may promote the opsonization of bacteria by adhering to the bacterial surface and acting as a target for antibody binding (157).…”

Section: The Emerging Picture Of Phage/immune Interactionsmentioning

confidence: 78%

Pf Bacteriophage and Their Impact on Pseudomonas Virulence, Mammalian Immunity, and Chronic Infections

et al. 2020

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Pf bacteriophage are temperate phages that infect the bacterium Pseudomonas aeruginosa, a major cause of chronic lung infections in cystic fibrosis (CF) and other settings. Pf and other temperate phages have evolved complex, mutualistic relationships with their bacterial hosts that impact both bacterial phenotypes and chronic infection. We and others have reported that Pf phages are a virulence factor that promote the pathogenesis of P. aeruginosa infections in animal models and are associated with worse skin and lung infections in humans. Here we review the biology of Pf phage and what is known about its contributions to pathogenesis and clinical disease. First, we review the structure, genetics, and epidemiology of Pf phage. Next, we address the diverse and surprising ways that Pf phages contribute to P. aeruginosa phenotypes including effects on biofilm formation, antibiotic resistance, and motility. Then, we cover data indicating that Pf phages suppress mammalian immunity at sites of bacterial infection. Finally, we discuss recent literature implicating Pf in chronic P. aeruginosa infections in CF and other settings. Together, these reports suggest that Pf bacteriophage have direct effects on P. aeruginosa infections and that temperate phages are an exciting frontier in microbiology, immunology, and human health.

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“…In addition, the potential for development of bacterial resistance is considered very low, due probably to the fact that they target the highly conserved peptidoglycan bonds [ 14 ]. For several endolysins, a synergistic effect with antibiotics has also been demonstrated [ 15 ]. Additionally, the efficacy of endolysins has been studied in various animal models of infection with promising results [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

Characterization of Clinical MRSA Isolates from Northern Spain and Assessment of Their Susceptibility to Phage-Derived Antimicrobials

et al. 2020

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Methicillin-resistant Staphylococcus aureus (MRSA) is a prevalent nosocomial pathogen, causing a wide range of diseases. The increased frequency of MRSA isolates in hospitals and the emergence of vancomycin resistance have sparked the search for new control strategies. This study aimed to characterize sixty-seven MRSA isolates collected from both infected patients and asymptomatic carriers in a Spanish hospital. RAPD-PCR allowed the identification of six genetic patterns. We also investigated the presence of genes involved in producing adhesins, toxins and the capsule; the biofilm; and antimicrobial resistance. A notable percentage of the isolates carried virulence genes and showed medium-high ability to form biofilms. Next, we assessed the strains’ susceptibility to two phages (phiIPLA-C1C and phiIPLA-RODI) and one endolysin (LysRODI). All strains were resistant to phiIPLA-C1C, and most (70.2%) were susceptible to phiIPLA-RODI. Regarding LysRODI, all strains displayed susceptibility, although to varying degrees. There was a correlation between endolysin susceptibility and the random amplification of polymorphic DNA (RAPD) profile or the presence of some virulence genes (fnbA, eta, etb, PVL and czr), but that was not observed with biofilm-forming ability, strain origin or phage sensitivity. Taken together, these findings can help to explain the factors influencing endolysin effectiveness, which will contribute to the development of efficient therapies targeting MRSA infections.

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Bactericidal Synergism Between Antibiotics and Phage Endolysin Cpl-711 to kill Multidrug-Resistant Pneumococcus

Cited by 50 publications

References 21 publications

Synergy Between Two Chimeric Lysins to Kill Streptococcus pneumoniae

Synergy Between Two Chimeric Lysins to Kill Streptococcus pneumoniae

Pf Bacteriophage and Their Impact on Pseudomonas Virulence, Mammalian Immunity, and Chronic Infections

Characterization of Clinical MRSA Isolates from Northern Spain and Assessment of Their Susceptibility to Phage-Derived Antimicrobials

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