Rethinking host range in polyvalent bacteriophages through a stochastic-cooperative hypothesis of receptor recognition.

As interest continues in bacteriophages as precision antimicrobials, understanding the molecular determinants of host range has become more important. Here, we use the term polyvalent to describe phages whose broad host recognition is associated with more than one receptor-binding protein (RBP) and/or more than one experimentally supported receptor-recognition pathway, which is distinct from broad host range as a phenotypic description alone. We propose a stochastic-cooperative hypothesis in which some RBPs can contribute primarily to reversible surface encounter and retention, whereas other RBPs mediate the stable receptor binding required to progress toward genome delivery. The novelty of this hypothesis is not the established reversible-to-irreversible sequence of adsorption, nor the existence of phages with multiple RBPs, but the specific prediction that functionally non-equivalent RBPs can alter the probability distribution of transitions between adsorption states on heterogeneous bacterial surfaces. Available structural, genetic, and single-particle evidence is consistent with parts of this interpretation but does not currently demonstrate a universal auxiliary-first pathway. Therefore, we distinguish evidence-supported elements from hypothetical components, consider alternative explanations for broad host range, and define experimentally testable predictions at molecular, single-particle, cellular, and population scales. This Perspective is intended as an experimentally evaluable conceptual model for studying how receptor density, accessibility, RBP composition, and post-adsorption barriers jointly shape observed host range, rather than as an established mechanism for all polyvalent phages.