Biology subjects

Maltas, J. A.

Publications and source records attributed to Maltas, J. A..

3 recordsLinked to original sources

bioRxiv2023

Heterogeneous collateral effects in daptomycin-resistant E. faecalis

Daptomycin, a cyclic lipopeptide antibiotic that targets the cell membrane, is an important therapeutic option for treating multi-drug-resistant infections, including vancomycin-resistant enterococci (VRE). Recent work has uncovered an array of daptomycin resistance mechanisms in enterococci, but relatively little is known about how these molecular defenses contribute to collateral effects-that is, to increased resistance or sensitivity to other drugs. In this work, we investigate collateral effects that arise during daptomycin adaptation of E. faecalis in four independent laboratory-evolved populations. Using a combination of growth assays and both single isolate and population sequencing, we identified DAP-resistant lineages with mutations in one or more genes previously associated with DAP resistance, and these isolates are characterized by divergent phenotypic properties-including different levels of DAP resistance and different growth rates (i.e. fitness costs) in drug-free media. Interestingly, we also observed strongly divergent collateral responses to different antibiotics, particularly CRO, with collateral resistance arising in mutants harboring DAP-resistance mutations in cardiolipin synthetase (cls) or in genes linked to the two-component signaling system YxdJK (bceR or a regulated transporter ycvR). By contrast, mutations in liaX, a component of a LiaFSR two-component signaling system, arose in two of the four populations, with point mutations associated with CRO-sensitivity and a large structural integration of plasmid pTEF3 associated with extreme CRO-sensitivity and a dramatically reduced growth rate. Our results reveal considerable phenotypic differences in mutations targeting the LiaSFR system and highlight trade-offs between resistance to daptomycin, collateral profiles (most notably to CRO), and drug-free growth rates in evolving lineages. As a whole, these results underscore how rich-and remarkably diverse-evolutionary dynamics can emerge even in parallel populations adapting to simple daptomycin escalation protocols.

evolutionary biology↗

bioRxiv2023

The evolution of diverse antimicrobial responses in vancomycin-intermediate Staphylococcus aureus and its therapeutic implications

Staphylococcus aureus bacteremia is typically treated empirically with vancomycin, with therapy later tailored based on susceptibility results. However, these tests occur before vancomycin exposure and do not account for adaptation during empiric treatment that can alter S. aureus susceptibility to first-line drugs. To investigate these collateral drug responses, we experimentally evolved 18 methicillin-susceptible S. aureus (MSSA) populations under increasing vancomycin concentrations until they achieved intermediate resistance. Genomic sequencing revealed two distinct adaptive pathways characterized by mutations in the WalKR regulon, affecting cell wall metabolism, or rpsU, impacting translational stress responses. These pathways correlated with divergent collateral sensitivity profiles to first-line antibiotics. By developing a Collateral Response Score (CRS), we quantified the probability and magnitude of these responses, demonstrating that evolutionary dynamics critically influence resistance outcomes. Our findings suggest a probabilistic approach to antimicrobial therapy, advocating for rapid genomic diagnostics alongside susceptibility testing to better anticipate and respond to evolutionary changes. SignificanceAntibiotic treatment can influence bacterial evolution, altering the effectiveness of subsequent therapies by inducing collateral resistance or sensitivity. This study reveals that evolution toward vancomycin-intermediate resistance in the pathogen Staphylococcus aureus proceeds through at least two distinct evolutionary pathways: one characterized by alterations in cell wall metabolism and another by changes in global stress response. These adaptive trajectories result in contrasting collateral sensitivities to first-line antibiotics. By introducing the Collateral Response Score, we assess the uncertainty in these outcomes, providing a probabilistic framework to evaluate how past antibiotic exposure shapes future treatment responses. Further validation studies are needed; however, we believe that improved forecasting of pathogen evolution can enhance antibiotic stewardship, inform therapeutic decisions, and ultimately improve patient outcomes.

evolutionary biology↗

bioRxiv2022

Fitness seascapes facilitate the prediction of therapy resistance under time-varying selection

Pharmacokinetic (PK) and pharmacodynamic (PD) modeling of host-pathogen interactions has enhanced our understanding of drug resistance. However, how combinations of drug resistance mutations impact dose-response curves remains underappreciated in PK-PD studies. The fitness seascape model addresses this by extending the fitness landscape model to map genotypes to dose-response functions, enabling the study of evolution under fluctuating drug concentrations. Here, we present an empirical fitness seascape in E. coli harboring all combinations of four drug resistance mutations. Incorporating these data into PK-PD simulations of antibiotic treatment, we find that higher mutation supply increases the probability of resistance, and early adherence to the drug regimen is critical. In vitro studies further support the finding that the second dose in a drug regimen is important for preventing resistance. This work represents the first application of an empirical fitness seascape in computational PK-PD studies, revealing novel insights into drug resistance.

evolutionary biology↗