Aminoglycoside Antibiotics Inhibit Phage Infection by Blocking an Early Step of the Infection Cycle

Abstract

Predation by phages is a major driver of bacterial evolution. As a result, elucidating antiphage strategies is crucial from both fundamental and therapeutic standpoints.

Antibiotics that affect translation can antagonize phage infectivity by interfering with the deployment of counter-defences

“…We also noted that in the case of Gm, a decline in phage titre was observed in the absence of CRISPR-Cas, and this was independent of the presence or absence of the phage acrIF1 gene (Figure 2A). This suggests that Gm causes an overall phage fitness decrease, in line with previous studies showing that aminoglycosides can inhibit phage infectivity 23,34,35 . Thus, these results show that the three translation inhibitors Chl, Ery and Tet interfere with the ability of DMS3 mvir -AcrIF1 to block CRISPR-Cas immunity.…”

“…This suggests that Gm interferes with phage amplification in a way that is independent of CRISPR-Cas and Acr, which results in a lesser impact on bacterial growth. Accordingly, the aminoglycosides antibiotic family, to which Gm belongs, has previously been reported to hinder phage production and favour bacterial growth when used at doses close or above the MIC 23,34,35 .…”

“…Sub-inhibitory doses of bacteriostatic antibiotics slow down both bacterial growth and phage replication, thereby lengthening the phage replication cycle and hence allowing more time for bacteria to acquire new spacers against the phage before being lysed. Phage-antibiotic interactions can range from synergy 21,22 to antagonism 23 . While often a mechanistic explanation for the observed interaction is lacking ( 24 and references herein), several different mechanisms have been identified, including antagonism caused by a decreased host RNA synthesis 25,26 and synergy mediated by phage-mediated impairment of antibiotic resistance development coupled by an antibiotic-mediated hindrance of phage resistance apparition 27 .…”

Discovery of phage determinants that confer sensitivity to bacterial immune systems

“…However, studies over the past few years have revealed a plethora of additional defense mechanisms commonly employed by bacteria. These include phage restriction by prokaryotic Argonaute proteins (Garb et al, 2021; Koopal et al, 2022; Kuzmenko et al, 2020; Zaremba et al, 2021), production of small molecules that block phage propagation (Bernheim et al, 2021; Kever et al, 2022; Kronheim et al, 2018), depletion of molecules essential for phage replication (Garb et al, 2021; Hsueh et al, 2022; Ofir et al, 2021; Tal et al, 2022), systems that use small molecule signaling to activate immune effectors (Cohen et al, 2019; Ofir et al, 2021; Tal et al, 2021; Whiteley et al, 2019), retrons that involve reverse transcription of non-coding RNAs (Bobonis et al, 2022; Gao et al, 2020; Millman et al, 2020), and more (Doron et al, 2018; Gao et al, 2020; Goldfarb et al, 2015; Johnson et al, 2022; Millman et al, 2022; Ofir et al, 2018; Rousset et al, 2022; Vassallo et al, 2022).…”

A Metabolite Produced by Gut Microbes Represses Phage Infections in Vibrio cholerae

“…These communities harbor a complex metabolic environment, including various secondary metabolites that can alter the physiology of the prey bacteria. , Additionally, these metabolites can alter phage infectivity. For example, anthracyclines and aminoglycosides produced by Streptomyces can directly interfere with phage reproduction in Escherichia coli , − while β-lactams can stimulate virulent phage proliferation in E. coli . Additionally, the metabolites mitomycin C, pyocyanin, and colibactin have been shown to trigger prophages in neighboring cells to enter their lytic cycles. − These findings suggest that environmental regulation of phage-host interactions by microbial metabolites could be common in nature.…”