Biology subjects

McCall, I. C.

Publications and source records attributed to McCall, I. C..

4 recordsLinked to original sources

bioRxiv2022

What the book of Lambda did not tell us about lysogens from natural populations

The most significant difference between bacteriophages functionally and ecologically is whether they are purely lytic (virulent) or temperate. Virulent phages can only be transmitted horizontally by infection, most commonly with the death of their hosts. Temperate phages can also be transmitted horizontally, but upon infection of susceptible bacteria, their genomes can be incorporated into that of their hosts as a prophage and be transmitted vertically in the course of cell division by their lysogenic hosts. From what we know from studies with the temperate phage Lambda and other temperate phages, in laboratory culture, lysogenic bacteria are protected from killing by the phage coded for by their prophage by immunity; where upon infecting lysogens, the free temperate phage coded by their prophage are lost. Why are lysogens not also resistant as well as immune to the phage coded by their prophage since immunity does not confer protection against virulent phages? To address this question, we used a mathematical model and performed experiments with temperate and virulent mutants of the phage Lambda in laboratory culture. Our models predict and experiments confirm that selection would favor the evolution of resistant as well as immune lysogens, particularly if the environment includes virulent phage that share the same receptors as the temperate. To explore the validity and generality of this prediction, we examined ten lysogenic Escherichia coli from natural populations. All ten were capable of forming immune lysogens but their original hosts were resistant to the phage coded by their prophage. Significance StatementThis jointly theoretical and experimental study predicted that lysogenic bacteria, will be resistant as well as immune to the phage coded for by their prophage. All ten naturally occurring lysogenic Escherichia coli tested were resistant to the temperate phage coded for by their prophage.

evolutionary biology↗

bioRxiv2020

Joint antibiotic and phage therapy: addressing the limitations of a seemingly ideal phage for treating Staphylococcus aureus infections

In response to increasing frequencies of antibiotic-resistant pathogens, there has been a resurrection of interest in the use of bacteriophage to treat bacterial infections: phage therapy. Here we explore the potential of a seemingly ideal phage, PYOSa, for combination phage and antibiotic treatment of Staphylococcus aureus infections. (i) This K-like phage has a broad host range; all 83 tested clinical isolates of S.aureus tested were susceptible to PYOSa. (ii) Because of the mode of action of PYOSa S. aureus is unlikely to generate classical receptor-site mutants resistant to PYOSa; none were observed in the 13 clinical isolates tested. (iii) PYOSa kills S. aureus at high rates. On the downside, the results of our experiments and tests of the joint action of PYOSa and antibiotics raise issues that must be addressed before PYOSa is employed clinically. Despite the maintenance of the phage, PYOSa does not clear the populations of S. aureus. Due to the ascent of a phenotypically diverse array of small colony variants following an initial demise, the bacterial populations return to densities similar to that of phage-free controls. Using a combination of mathematical modeling and in vitro experiments, we postulate and present evidence for a mechanism to account for the demise-resurrection dynamics of PYOSa and S. aureus. Critically for phage therapy, our experimental results suggest that treatment with PYOSa followed by bactericidal antibiotics can clear populations of S. aureus more effectively than the antibiotics alone. Significance StatementThe increasing frequency of antibiotic-resistant pathogens has fostered a quest for alternative means to treat bacterial infections. Prominent in this quest is a therapy that predates antibiotics: bacteriophage. This study explores the potential of a phage, PYOSa, for treating Staphylococcus aureus infections in combination with antibiotics. On first consideration, this phage, isolated from a commercial therapeutic cocktail, seems ideal for this purpose. The results of this population dynamic and genomic analysis study identify a potential liability of using PYOSa for therapy. Due to the production of potentially pathogenic atypical small colony variants, PYOSa alone cannot eliminate S. aureus populations. However, we demonstrate that by following the administration of PYOSa with bactericidal antibiotics, this limitation and potential liability can be addressed.

microbiology↗

bioRxiv2019

The population and evolutionary dynamics of bacteriophage: Why be temperate revisited

Bacteriophages are deemed either lytic (virulent) or temperate, respectively depending on whether their genomes are transmitted solely horizontally, or both horizontally and vertically. To elucidate the ecological and evolutionary conditions under which natural selection will favor the evolution and maintenance of lytic or temperate modes of phage replication and transmission, we use a comprehensive mathematical model of the dynamics of temperate and virulent phage in populations of bacteria sensitive and resistant to these viruses. For our numerical analysis of the properties of this model, we use parameters estimated with the temperate bacteriophage Lambda, {lambda}, its clear and virulent mutants, and E. coli sensitive and resistant - refractory to these phages. Using batch and serial transfer population dynamic and reconstruction experiments, we test the hypotheses generated from this theoretical analysis. Based on the results of this jointly theoretical and experimental study, we postulate the conditions under which natural selection will favor the evolution and maintenance of lytic and temperate modes of phage replication and transmission. A compelling and novel prediction this in silico, in vitro, and in plastico study makes is lysogenic bacteria from natural populations will be resistant-refractory to the phage for which they are lysogenic as well as lytic phage sharing the same receptors as these temperate viruses.

evolutionary biology↗

bioRxiv2018

Antibiotic killing of diversely generated populations of non-replicating bacteria

Non-replicating bacteria are known to be (or at least commonly thought to be) refractory to antibiotics to which they are genetically susceptible. Here, we explore the sensitivity to antibiotic-mediated killing of three classes of non-replicating populations of planktonic bacteria (1) stationary phase, when the concentration of resources and/or nutrients are too low to allow for population growth; (2) persisters, minority subpopulations of susceptible bacteria surviving exposure to bactericidal antibiotics; (3) antibiotic-static cells, bacteria exposed to antibiotics that prevent their replication but kill them slowly if at all, the so-called bacteriostatic drugs. Using experimental populations of Staphylococcus aureus Newman and Escherichia coli K12 and respectively 14 and 11 different antibiotics, we estimate the rates at which these drugs kill these different types of non-replicating bacteria. Contrary to the common belief that bacteria that are non-replicating are refractory to antibiotic-mediated killing, all three types of non-replicating populations of these Gram-positive and Gram-negative bacteria are consistently killed by aminoglycosides and the peptide antibiotics, daptomycin and colistin, respectively. This result indicates that non-replicating cells, irrespectively of why they do not replicate, have an almost identical response to the cidal activity of antibiotics. We discuss the implications of these results to our understanding of the mechanisms of action of antibiotics and the possibility of adding a short-course of aminoglycosides or peptide antibiotics to conventional therapy of bacterial infections.

microbiology↗