Preferential Selection of Low-Frequency, Lipopolysaccharide-Modified, Colistin-Resistant Mutants with a Combination of Antimicrobials in Acinetobacter baumannii

Abstract

Acinetobacter baumannii has developed resistance to various antimicrobial drugs, and its drug-resistant strains cause nosocomial infections. Controlling these infections has become a global clinical challenge.

Colistin Resistance in Acinetobacter baumannii: Molecular Mechanisms and Epidemiology

“…The proposed explanation for the lower prevalence of LPS-deficient colistin-resistant mutants in clinical settings could be the significant negative impact of LPS loss on fitness and virulence, as well as the susceptibility of these isolates to various antibiotics and disinfectants. This was supported by the findings that the lpx mutants grew more slowly compared to the parental wild-type strains in vitro [ 64 , 66 , 68 , 81 , 83 ], while in vitro and in vivo competition tests showed significant fitness costs of colistin resistance [ 81 ]. Determination of the pathogenicity of the lpx mutants also revealed lower cytotoxicity (A549 human alveolar epithelial cells) and attenuated virulence of these strains in the animal models ( Caenorhabditis elegans, Galleria mellonella, and mouse) compared to wild-type or even pmrB mutants [ 63 , 66 , 81 ].…”

“…Accordingly, pmrB mutations could lead to the constitutive activation of PmrA, resulting in increased expression of the pmrCAB and resistance to colistin [ 59 ]. In addition, previous studies reported frequent amino acid substitutions of PmrB at position 170 (P to Y, L, Q, or S) ( Table 1 ) and 315 (G to D, S, or V) in colistin-resistant isolates [ 68 , 70 , 76 , 84 , 86 ]. Although Oikonomou and coauthors [ 69 ] described the PmrB mutations (A138T, A226V, and A444V) repeated in colistin-resistant A. baumannii [ 70 , 72 , 73 , 74 , 76 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 ] as not responsible for colistin resistance, the involvement of A138T and A226V in this phenomenon should not be excluded.…”

“…In subsequent studies, the insertion of IS Aba1 or IS Aba11 within the lpxC gene was described as a common event in colistin-resistant A. baumannii . As the disruption of the lpxC gene occurred in the same region (321–420 nt) in different isolates, it was suggested that this region might represent a hot spot for the integration of ISs [ 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 ]. Colistin resistance in A. baumannii has also been associated with various nucleotide substitutions, deletions, and insertions in all three lipid A biosynthetic genes ( lpxA , lpxC, or lpxD ) that cause frameshifts or result in truncated proteins that impair lipid A biosynthesis.…”

“…Although the amino acid substitutions N287D ( lpxC ) and E117K ( lpxD ) were detected in both colistin-susceptible and colistin-resistant isolates, it is possible that these alterations in combination with a mutation in the pmrCAB operon have a synergistic effect leading to colistin resistance [ 69 , 70 , 71 , 72 , 73 , 74 ]. In addition, the downregulation of lpxACD expression has been observed in some colistin-resistant A. baumannii isolates, leading to decreased LPS production [ 68 , 73 , 74 , 75 , 76 ].…”

“…Moreover, reduced virulence of LPS-deficient A. baumannii in the host could also be explained by reduced biofilm formation, surface motility, as well as poor growth under iron limitation [ 66 , 83 ]. Finally, another disadvantage of LPS loss for the bacterial cell is evident in the increased susceptibility to various clinically used antibiotics, especially antibiotics used in the therapy of A. baumannii infections (ceftazidime, imipenem, meropenem, tigecycline, ciprofloxacin, amikacin, and rifampin), and various disinfectants (phenol-based disinfectants, quaternary ammonium disinfectants, sodium dodecyl sulfate, benzalkonium, chlorhexidine, deoxycholate, and ethanol) [ 58 , 63 , 64 , 65 , 66 , 68 , 83 ].…”