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.
The tail fiber adhesins are the primary determinants of host range in the T4-type bacteriophages. Among the indispensable virion components, the sequences of the long tail fiber genes and their associated adhesins are among the most variable. The predominant form of the adhesin in the T4-type phages is not even the version of the gene encoded by T4, the archetype of the superfamily, but rather a small unrelated protein (gp38) encoded by closely related phages such as T2 and T6. This gp38 adhesin has a modular design: its N-terminal attachment domain binds at the tip of the tail fiber, whereas the C-terminal specificity domain determines its host receptor affinity. This specificity domain has a series of four hypervariable segments (HVSs) that are separated by a set of highly conserved glycine-rich motifs (GRMs) that apparently form the domain’s conserved structural core. The role of gp38’s various components was examined by a comparative analysis of a large series of gp38 adhesins from T-even superfamily phages with differing host specificities. A deletion analysis revealed that the individual HVSs and GRMs are essential to the T6 adhesin’s function and suggests that these different components all act in synergy to mediate adsorption. The evolutionary advantages of the modular design of the adhesin involving both conserved structural elements and multiple independent and easily interchanged specificity determinants are discussed.
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