3 research outputs found
Multidrug-resistant enterobacterales in Oman : molecular epidemiology and therapeutic insights
The spread of antibiotic resistance is a concerning issue causing limited treatment options for
bacterial infections, particularly with Gram-negative bacteria. Surveillance and
epidemiological studies help to determine the magnitude of the problem as well as to
establish early measures to slow down the spread of resistance and consequently increase
antibiotic lifespan. Currently, there is a visible paucity of published data about resistance
from the Arabian Peninsula. In this thesis, we studied a collection of carbapenem nonsusceptible
E. coli (n=35) and K. pneumoniae (n=237) isolated in 2015 from various hospitals
in Oman. We aimed at identifying resistance mechanisms, mapping the bacterial population
structure, investigating bacterial fitness, and studying potential treatment options available to
tackle infections caused by such multidrug-resistant strains. These aims were addressed in
five papers as discussed below.
NDM and OXA-48 were the only carbapenemases we found in this collection, both among
E. coli (Paper I) and K. pneumoniae (Paper II). The pattern of resistance among the isolates
from Arabian Peninsula mimics the pattern reported from the Indian subcontinent, most
likely due to the close socioeconomic interactions between them. Both regions lack KPC
enzymes, which are commonly seen in China and the US from strains belong to ST11 and
ST258, respectively. Despite ST11 being predominant in this collection, we did not detect
KPC. Yet, we detected a high-risk clone of E. coli, ST131-H30Rx-CTX-M-15. Additionally,
we identified newly emerging clones of K. pneumoniae and E. coli such as ST231 and
ST1193-H64RxC, respectively.
Nearly 10% of the K. pneumoniae isolates in our collection were colistin resistant which
prompted us to study the mechanisms of colistin resistance (Paper III). MgrB-inactivation
by insertion elements was seen in 8 isolates while other mutations were seen in other
chromosomal genes known to be involved in colistin resistance e.g. pmrB, phoPQ and crrB.
However, we did not detect mcr genes. Collectively, the genetic alterations are thought to
reduce the net negative charge in bacterial cell wall, hence lowering the binding affinity of
colistin. Our data underscores that there is no reduction in the surface charge in colistinresistant
K. pneumoniae, due to the MgrB-insertion (Paper IV). The genetic alteration might
lead to other structural changes in the cell wall such as altering hydrophobicity, which
required further investigation. Also, our data shows no difference in the survival rates of
colistin resistant and susceptible strains in blood, serum and zebrafish model. Thus, gaining
resistance against colistin does not infer a fitness cost in K. pneumoniae with MgrB-insertion
(Paper IV). Additionally, colistin and LL-37 share similar binding mechanism which suggest
there might be a cross-resistance between them. Our data supported this hypothesis, but only
at high concentrations of LL-37 ( ≥ 50 mg/L) (Paper IV).
Finally, we studied available options to treat infections caused by multidrug-resistant strains.
Combining colistin and rifampicin showed good in vitro activity against multidrug-resistant
strains of E. coli (Paper V) and K. pneumoniae (Paper III). To summarise, we conducted
comprehensive genomic analysis of E. coli and K. pneumoniae isolates from Oman to reveal
the resistance mechanism, their impact on bacterial cell structural and if there is a fitness cost
inferred by the resistance mechanisms. Finally, we studied combination therapy as an
available option at hand for tackling infections caused by multidrug-resistant strains