Phage-Antibiotic Synergy (PAS): β-Lactam and Quinolone Antibiotics Stimulate Virulent Phage Growth

Abstract

Although the multiplication of bacteriophages (phages) has a substantial impact on the biosphere, comparatively little is known about how the external environment affects phage production. Here we report that sub-lethal concentrations of certain antibiotics can substantially stimulate the host bacterial cell's production of some virulent phage. For example, a low dosage of cefotaxime, a cephalosporin, increased an uropathogenic Escherichia coli strain's production of the phage ΦMFP by more than 7-fold. We name this phenomenon Phage-Antibiotic Synergy (PAS). A related effect was observed in diverse host-phage systems, including the T4-like phages, with β-lactam and quinolone antibiotics, as well as mitomycin C. A common characteristic of these antibiotics is that they inhibit bacterial cell division and trigger the SOS system. We therefore examined the PAS effect within the context of the bacterial SOS and filamentation responses. We found that the PAS effect appears SOS-independent and is primarily a consequence of cellular filamentation; it is mimicked by cells that constitutively filament. The fact that completely unrelated phages manifest this phenomenon suggests that it confers an important and general advantage to the phages.

Rapid evolution of generalized resistance mechanisms can constrain the efficacy of phage–antibiotic treatments

“…This is in contrast with previous studies reporting beneficial effects of phage–antibiotic combinations on Escherichia coli biofilms (Ryan, Alkawareek, Donnelly, & Gilmore, 2012) and planktonic P. aeruginosa cultures (Torres‐Barceló et al., 2016). However, phage–antibiotic effects are not always observed (Verma et al., 2009), which could be due to the specific phage species and class of antibiotic as PAS often requires mechanistic compatibility between the two (Chan et al., 2016; Comeau et al., 2007; Kamal & Dennis, 2015). For example, it has recently been reported that associations between phage and gentamycin resistance are predominantly positive, while associations between phage and ciprofloxacin resistance are mainly negative with natural and clinical E. coli isolates (Allen, Pfrunder‐Cardozo, Meinel, Egli, & Hall, 2017).…”

“…Positive correlation between phage selection and antibiotic resistance is in contrast with previous studies showing an opposite effect where phage treatment reduced the emergence of antibiotic resistance (Jalasvuori, Friman, Nieminen, Bamford, & Buckling, 2011; Zhang & Buckling, 2012). One explanation for this discrepancy is that phage–antibiotic synergies could be very specific to the given phage species and type of antibiotics, whereas antibiotic selection‐mediated susceptibility to phages could have been driven by some degree of collateral sensitivity (Chan et al., 2016; Comeau et al., 2007; Kamal & Dennis, 2015). …”

“…Additive effects are expected when phage and antibiotic work independently of each other, and their combined effect is the sum of their independent effects. In the case of synergistic effects, phage–antibiotic combinations are often observed to have more detrimental (or less detrimental) effects on the pathogenic bacteria than would be expected based on the sum of their independent effects (Comeau, Tétart, Trojet, Prère, & Krisch, 2007; Hagens, Habel, & Blasi, 2006; Huff, Huff, Rath, Balog, & Donoghue, 2004). PAS is thought to occur because two sufficiently different selective pressures are more likely to kill both nonresistant (susceptible to antibiotics) and antibiotic‐resistant (susceptible to phages) pathogen genotypes (Torres‐Barceló & Hochberg, 2016).…”

La « synergie phages-antibiotiques »

“…La phagothé-rapie a cependant continué d'exister jusqu'à ce jour en ex-Union soviétique, en particulier en République de Géor-gie, grâce à l'Institut George Eliava cofondé par d'Hérelle et Eliava dans les années 1920 [7]. [9]. L'addition à des cultures bactériennes de faibles doses d'antibiotiques qui bloquent la division cellulaire et induisent la formation de filaments, comme le font les céphalosporines, augmente de façon significative la production de phages.…”

La phagothérapie

“…croissant de travaux souligne une synergie d'action entre phage et antibiotique, notamment en présence de concentration sub-inhibitrice d'antibiotique, comme rencontré dans le cas d'infections avec des souches de sensibilité intermédiaire aux antibiotiques [21].…”