Key role of quorum‐sensing mutations in the development of Staphylococcus aureus clinical device‐associated infection

Abstract

Dear Editor, In the present study, we show that the development of Staphylococcus aureus device-associated infection involves mutations in the quorum-sensing system Agr that increase biofilm formation and thereby bacterial resistance to antibiotics.The enormous difficulty clinicians face in the treatment of device-associated infections is due to the characteristic involvement of biofilms, which are bacterial agglomerations that form on the device surface and exhibit considerably increased resistance to virtually all types of antibiotics. 1 One of the most frequent causes of deviceassociated infections is Staphylococcus aureus, which is also infamous for its exceptional recalcitrance towards antibiotic treatment. 2,3 How device-associated infections develop remains incompletely understood. This is in part since only end-point isolates from clinical deviceassociated infection are usually investigated. Main questions that remain include whether a device-associated infection is only caused by a selection of strains that are particularly pronounced biofilm formers or whether adaptations increasing biofilm formation occur during infection, and if so, which among them play a dominant role for that adaptation.To answer these questions, we compared sequential isolates from cases of prolonged S. aureus surgical implant infection obtained at our hospital (See Figure S1 for selection of isolates). In all cases, initial (T1) samples were taken after infection had developed post-surgery, and secondary (T2) samples were collected when recurrence or persistence of infection was diagnosed (Table S1). All bacterial samples from the T1 and T2 time points were classified as S. aureus by appearance and mass spectrometry. Remarkably, all T1 isolates were homogenously hemolytic on sheep blood agar plates, whereas all T2 samples were homogenously non-hemolytic (Figure 1A). One representative clone of each sample was stored, and all stored T1 and T2 isolates were confirmed to exhibit a hemolyticThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Critical Assessment of the Prospects of Quorum-Quenching Therapy for Staphylococcus aureus Infection

“…Contrastingly, Agr has the opposite effect on infections that are chronic and involve biofilms, such as infections of indwelling medical devices, prosthetic joint infections, or cystic fibrosis [ 19 , 41 , 42 , 43 ]. It also, somewhat paradoxically, promotes persistence in osteomyelitis [ 44 ].…”

“…This is often due to its exceptionally strict control of PSMs, which structure biofilms and lead to biofilm dispersal [ 45 ], and facilitate escape from host cells [ 46 ]. In the absence of PSMs in Agr dysfunctional mutants, biofilms grow thicker and more compact, which leads to increased resistance to leukocyte attacks and antibiotics [ 42 , 43 ]. In many host cells, the absence of Agr-controlled factors, including PSMs, leads to intercellular persistence [ 47 , 48 ].…”

“…In many host cells, the absence of Agr-controlled factors, including PSMs, leads to intercellular persistence [ 47 , 48 ]. The natural occurrence of Agr dysfunctional mutants has been observed for a long time and recently, their rise could be directly linked to the persistence of biofilm infections on indwelling devices [ 43 ].…”

Repurposed Fenoprofen Targeting SaeR Attenuates Staphylococcus aureus Virulence in Implant-Associated Infections

“…18 Dysfunctional mutations of the agr system help to suppress S. aureus skin and intestinal colonization, 19,20 which are nonimplant-associated infections. However, we recently found that S. aureus agr-dysfunctional mutants could be isolated from clinical cases of surgical implant-associated infection 21 and that prolonged infection increased the rate of agr-dysfunctional mutant development. Our previous in vivo observations revealed that agr-dysfunctional isolates could form robust and enlarged biofilms on the implant surface to increase the resistance of agr-dysfunctional biofilms to leukocyte attacks.…”

Quorum-sensing, intra- and inter-species competition in the staphylococci

“…However, while these data provide an explanation for mixed populations in toxigenic infections, they do not account for chronic, biofilm-associated clinical S. aureus infections where homogeneous agr -negative populations can rapidly emerge [112]. It should also be noted that S.…”